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WO2025147609A1 - Amino quinoline compounds and uses thereof - Google Patents

Amino quinoline compounds and uses thereof Download PDF

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Publication number
WO2025147609A1
WO2025147609A1 PCT/US2025/010234 US2025010234W WO2025147609A1 WO 2025147609 A1 WO2025147609 A1 WO 2025147609A1 US 2025010234 W US2025010234 W US 2025010234W WO 2025147609 A1 WO2025147609 A1 WO 2025147609A1
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Prior art keywords
membered
compound
pharmaceutically acceptable
optionally substituted
6alkyl
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PCT/US2025/010234
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French (fr)
Inventor
Eric Riguet
Michael Wagner
Eduardo J. Martinez
Hector Manuel TORRES GOMEZ
Andreas Thomas ZECH
Jesse Derek LAI
Violeta Yu
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Dewpoint Therapeutics Inc
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Dewpoint Therapeutics Inc
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Publication of WO2025147609A1 publication Critical patent/WO2025147609A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • condensate dysfunction in ALS pathogenesis is supported by the discovery of condensate genes as genetic modifiers of ALS (e.g., TAF15, EWSR1, TIA1, HNRNPA1, HNRNPA2B1), as well as co-localization of C9ORF72 ALS G 4 C 2 expansion- derived dipeptide repeats (DPRs) and stress granule proteins with TDP-43 inclusions in preclinical models. Nuclear depletion of TDP-43 into cytoplasmic condensates leads to toxic loss of splicing function in motor neurons.
  • condensate genes as genetic modifiers of ALS (e.g., TAF15, EWSR1, TIA1, HNRNPA1, HNRNPA2B1), as well as co-localization of C9ORF72 ALS G 4 C 2 expansion- derived dipeptide repeats (DPRs) and stress granule proteins with TDP-43 inclusions in preclinical models.
  • DPRs expansion- derived dipeptid
  • This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III- A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing.
  • a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.
  • This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing.
  • This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • I n one aspect, provided herein is a method of modulating TDP-43, comprising contacting a cell with an effective amount of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing.
  • This aspect in some embodiments may employ a Attorney Docket No.: 185992002240 compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III- A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing.
  • a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in the treatment of a disease or condition mediated by TDP-43.
  • This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing.
  • a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in the treatment of a disease or condition mediated by TDP-43.
  • This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients, in the manufacture a medicament for the treatment of a disease or condition mediated by TDP-43.
  • kits comprising (i) a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating a TDP-43 mediated disease or condition in an individual in need thereof.
  • This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • “Individual” refers to mammals and includes humans and non-human mammals. Examples of individuals include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, individual refers to a human. As used herein, “about” a parameter or value includes and describes that parameter or value per se. For example, “about X” includes and describes X per se. “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results.
  • Beneficial or desired results may include one or more of the following: decreasing one or more symptom resulting from the disease or condition; diminishing the extent of the disease or condition; slowing or arresting the development of one or more symptom associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition); and relieving the disease, such as by causing the regression of clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival).
  • “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition.
  • This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.
  • the term “therapeutically effective amount” or “effective amount” intends such amount of a compound of the disclosure or a pharmaceutically salt thereof sufficient to effect treatment when administered to an individual. As is understood in the art, an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • an effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • unit dosage form refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient, or compound, which may be in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects.
  • alkyl residue having a specific number of carbons When an alkyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “butyl” includes n-butyl, sec-butyl, iso-butyl, and tert-butyl; and “propyl” includes n-propyl and iso- propyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkyl” group, may be referred to as an “alkylene”.
  • alkenyl examples include, but are not limited to, ethenyl, prop-1-enyl, prop-2-enyl 1,2- butadienyl, and 1,3-butadienyl.
  • alkenyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propenyl” includes prop-1- enyl and prop-2-enyl.
  • a divalent group such as a divalent “alkenyl” group, may be referred to as an “alkenylene”.
  • alkynyl refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon triple bond.
  • alkynyl has 2-20 carbons (i.e., C2-20alkynyl), 2-16 carbons (i.e., C2-16alkynyl), 2-12 carbons (i.e., C 2-12 alkynyl), 2-10 carbons (i.e., C 2-10 alkynyl), 2-8 carbons (i.e., C 2-8 alkynyl), 2-6 carbons (i.e., C 2-6 alkynyl), 2-4 carbons (i.e., C 2-4 alkynyl), or 2-3 carbons (i.e., C 2-3 alkynyl).
  • alkynyl examples include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1- ynyl, but-2-ynyl, and but-3-ynyl.
  • alkynyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propynyl” includes prop-1- ynyl and prop-2-ynyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art.
  • alkoxy refers to an -O-alkyl moiety.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • aryl refers to a fully unsaturated carbocyclic ring moiety.
  • aryl encompasses monocyclic and polycyclic fused-ring moieties.
  • aryl encompasses ring moieties comprising, for example, 6 to 20 annular carbon atoms (i.e., 6- to 20-membered aryl), 6 to 16 annular carbon atoms (i.e., 6- to 16-membered aryl), 6 to 12 annular carbon atoms (i.e., 6- to 12-membered aryl), or 6 to 10 annular carbon atoms (i.e., 6- to 10-membered aryl).
  • aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.
  • cycloalkyl refers to a saturated or partially unsaturated carbocyclic ring moiety.
  • cycloalkyl encompasses monocyclic and polycyclic ring moieties, wherein the polycyclic moieties may be fused, branched, or spiro.
  • Cycloalkyl includes cycloalkenyl groups, wherein the ring moiety comprises at least one annular double bond. Cycloalkyl includes any polycyclic carbocyclic ring moiety comprising at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule.
  • cycloalkyl includes rings comprising, for example, 3 to 20 annular carbon atoms (i.e., a C3-20cycloalkyl), 3 to 16 annular carbon atoms (i.e., a C3-16cycloalkyl), 3 to 12 annular carbon atoms (i.e., a C3-12cycloalkyl), 3 to 10 annular carbon atoms (i.e., a C3-10cycloalkyl), 3 to 8 annular carbon atoms (i.e., a C 3-8 cycloalkyl), 3 to 6 annular carbon atoms (i.e., a C 3- 6cycloalkyl), or 3 to 5 annular carbon atoms (i.e., a C3-5cycloalkyl).
  • 3 to 20 annular carbon atoms i.e., a C3-20cycloalkyl
  • 3 to 16 annular carbon atoms i.e., a C3-16cycloalkyl
  • Monocyclic cycloalkyl ring moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbonyl, decalinyl, 7,7-dimethyl -bicyclo [2.2.1]heptanyl, and the like.
  • cycloalkyl also includes spiro cycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5]undecanyl.
  • halo refers to atoms occupying groups VIIA of The Periodic Table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).
  • terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • C 1-4 haloalkyl is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like.
  • heteroaryl includes both monocyclic and polycyclic fused-ring moieties.
  • a heteroaryl comprises, for example, 5 to 20 annular atoms (i.e., a 5- to 20-membered heteroaryl), 5 to 16 annular atoms (i.e., a 5- to 16-membered heteroaryl), 5 to 12 annular atoms (i.e., a 5- to 12-membered heteroaryl), 5 to 10 annular atoms (i.e., a 5- to 10-membered heteroaryl), 5 to 8 annular atoms (i.e., a 5- to 8-membered heteroaryl), or 5 to 6 annular atoms (i.e., a 5- to 6-membered heteroaryl).
  • 5 to 20 annular atoms i.e., a 5- to 20-membered heteroaryl
  • 5 to 16 annular atoms i.e., a 5- to 16-membered heteroaryl
  • 5 to 12 annular atoms i.e., a 5- to 12-membered heteroaryl
  • heteroaryl Any monocyclic or polycyclic aromatic ring moiety comprising one or more annular heteroatoms is considered a heteroaryl, regardless of the point of attachment to the remainder of the molecule (i.e., the heteroaryl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heteroaryl moiety).
  • heteroaryl groups include, but are not limited to, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and pyridazinyl.
  • a heterocyclyl comprises, for example, 3 to 20 annular atoms (i.e., a 3- to 20-membered heterocyclyl), 3 to 16 annular atoms (i.e., a 3- to 16- membered heterocyclyl), 3 to 12 annular atoms (i.e., a 3- to 12-membered heterocyclyl), 3 to 10 annular atoms (i.e., a 3- to 10-membered heterocyclyl), 3 to 8 annular atoms (i.e., a 3- to Attorney Docket No.: 185992002240 8-membered heterocyclyl), 3 to 6 annular atoms (i.e., a 3-6 membered heterocyclyl), 3 to 5 annular atoms (i.e., a 3- to 5-membered heterocyclyl), 5 to 8 annular atoms (i.e., a 5- to 8- membered heterocyclyl), or 5 to 6 annular atom
  • heterocyclyl groups include, e.g., azetidinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, or tetrahydropyranyl.
  • spiro heterocyclyl rings include, but are not limited to, bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1- azaspiro[3.3]heptanyl.
  • fused heterocyclyl rings include, but are not limited to, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinyl, 5,7- dihydrofuro[3,4-d]pyrimidinyl, and 5,7-dihydrothieno[3,4-d]pyrimidinyl, where the heterocyclyl can be bound via either ring of the fused system.
  • bridged refers to a polycyclic moiety in which two of the rings share three or more atoms in common, and the bridgehead atoms are separated by at least one atoms.
  • bridged may refer to a saturated or partially unsaturated carbocycle, or a saturated or partially unsaturated heterocycle.
  • optional and “optionally”, as used herein, mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not.
  • any one or more (e.g., 1, 2, 1 to 5, 1 to 3, 1 to 2, etc.) hydrogen atoms on the designated atom or moiety or group may be replaced or not replaced by an atom or moiety or group other than hydrogen.
  • the phrase “methyl optionally substituted with one or more chloro” encompasses -CH3, -CH2Cl, -CHCl2, and -CCl3 moieties. It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments.
  • “pharmaceutically acceptable salt”, as used herein, of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable.
  • “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt, particularly a pharmaceutically acceptable addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, trifluoroacetic acid, and the like.
  • pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases.
  • Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines.
  • suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N- ethylpiperidine, and the like. Isotopically labeled forms of the compounds depicted herein may be prepared.
  • Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • a compound of formula (I) is provided wherein one or more hydrogen is replaced by deuterium or tritium.
  • Tautomers are in equilibrium with one another.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds of this disclosure are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, for example, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, imidic-acid containing compounds are understood to include their amide tautomers.
  • prodrugs of the compounds depicted herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof are also provided herein.
  • Prodrugs are compounds that may be administered to an individual and release, in vivo, a compound depicted herein as the parent drug compound. It is understood that prodrugs may be prepared by modifying a functional group on a parent drug compound in such a way that the modification is cleaved in vitro or in vivo to release the parent drug compound.
  • the compounds of the present disclosure, or their pharmaceutically acceptable salts, hydrates, or solvates may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- (or as (D)- or (L)- for amino acids).
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, for example, chromatography and/or fractional crystallization.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC), and chiral supercritical fluid chromatography (SFC).
  • the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • R 1 and R 2 are each independently C 1-6 alkyl, C 2-6 alkenyl, or C 3-8 cycloalkyl, wherein t he C1-6alkyl of R1 or R2 is optionally substituted with one or more R1a, the C3-8cycloalkyl of R 1 or R2 is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, or C3-8cycloalkyl group of R 1 or R 2 are taken together with the atoms to which they are attached to form a C3-
  • the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • R 1 and R 2 are each independently C1-6alkyl, C2-6alkenyl, or C3-8cycloalkyl, wherein t he C1-6alkyl of R1 or R2 is optionally substituted with one or more R1a, the C 3-8 cycloalkyl of R 1 or R2 is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, or C3-8cycloalkyl group of R 1 or R 2 are taken together with the atoms to which they are attached to form a C3- 8
  • the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • R 1 and R 2 are each independently C 1-6 alkyl optionally substituted with one or more R 1a ; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, oxo, -OR 12 , or -N(R x )(R y ) wherein the C 1-6 alkyl of R 3 is optionally substituted with R 3a ; Ring A is 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl,
  • the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • R1 and R2 are taken together with the N to which they are attached to form a saturated 4- to 5- membered monocyclic heterocyclyl, saturated 7- to 10-membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl, wherein Attorney Docket No.: 185992002240 the saturated 4- to 5-membered monocyclic heterocyclyl, saturated 7- to 9-membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl is optionally substituted with one or more R 3 ; each R 3 is independently halo, C 1-6 alkyl, oxo, -OR 12 , -N(R x )(R y ), -CN,
  • R 1 and R 2 are each independently C 1-6 alkyl optionally substituted with one or more R 1a ; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, oxo, -OR 12 , or -N(R x )(R y ) wherein the C1-6alkyl of R 3 is optionally substituted with R 3a ; Ring A is 4- to 8-membered monocyclic cycloalkenyl, 4- to 8-membered unsaturated monocyclic heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 8-membered
  • the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • R 1 and R 2 are each independently C 1-6 alkyl optionally substituted with one or more R 1a ; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, oxo, -OR 12 , or -N(R x )(R y ) wherein the C 1-6 alkyl of R 3 is optionally substituted with R 3a ; Ring A is 4- to 8-membered monocyclic cyclo
  • the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • Attorney Docket No.: 185992002240 In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R 1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R 3 ; R 8 is H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(O)R14, -N(R13)C(O)OR14, - N(R13)C(O)N(R13)R14, -C(O)N(R13)(R14), or C3-6cyclo
  • the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • R 1 and R2 are taken together with the N to which they are attached to form a 4- to 12- membered heterocyclyl optionally substituted with one or more R 3 ;
  • Ring A is pyridinyl; and
  • L is a bond or -O-(C1-6alkyl)-.
  • the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • R 1 and R2 are taken together with the N to which they are attached to form a 4- to 12- membered heterocyclyl optionally substituted with one or more R 3 ; Ring A is pyridinyl; L is a bond; and R 6 is piperazinyl optionally substituted with one or more R6b.
  • the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing Attorney Docket No.: 185992002240 R 1 and R2 are taken together with the N to which they are attached to form a 4- to 12- membered heterocyclyl optionally substituted with one or more R 3 ; and R 8 and R9 are each independently H, F, -N(CH3)(CH3), -OCH3 or -OCD3.
  • the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • Ring A is phenyl and R 6 is selected from the group consisting of -NH 2 , - NHCH3, and -N(CH3)3, R 1 and R 2 are not both C1-2alkyl;
  • R 1 and R 2 are taken together with the N to which they are attached to form a 4-methylpiperazinyl, -(Ring A)-X-L-R6 is not
  • -(Ring A)-X-L-R6 is not
  • R 6 is not selected from the group consisting of -NH2, -NHC(O)CH3, and -NHC(O)O-C(CH 3 ) 3 ; and
  • Ring A is pyridin-4yl substituted with -NH
  • Ring A when Ring A is phenyl, then -L-R 6 is not -NH 2 or -OCH 3 .
  • Ring A is phenyl or 5- to 6-membered heteroaryl.
  • Ring A is selected from the group consisting of phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furan, thiophene, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • Ring A is phenyl, thiazolyl, or pyridinyl.
  • Ring A is 4- to 8-membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 8- membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6- membered heteroaryl of Ring A is optionally substituted by one or more R4; and the 4- to 8- membered unsaturated heterocyclyl or 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S.
  • Ring Attorney Docket No.: 185992002240 A is phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4; and the 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S.
  • Ring A is phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4.
  • R 1 and R 2 are each independently C 1-6 alkyl optionally substituted with one or more R1a. In some embodiments, R1 and R2 are each independently C1-4alkyl optionally substituted with one or more R 1a .
  • Step 5 To a mixture of tert-butyl N-[2-[(5-bromo-2-pyridyl)oxy]ethyl]-N- cyclopropyl-carbamate 10.5 (0.60 g, 1.4 mmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (0.44 g, 1.7 mmol, 1.2 eq) in dioxane (10 mL) were added 1,1-bis(diphenylphosphino)ferrocene palladium(II)dichloride (53 mg, 0.07 mmol, 0.05 eq) and potassium acetate (0.28 g, 2.9 mmol, 2.0 eq) at 25 °C.
  • Step 2 To a solution of 5-bromo-2-iodo-pyridine 11.3 (9.7 g, 34 mmol, 1.0 eq) in THF (150 mL) was added tert-butyl N-[2-[methoxy(methyl)amino]-1-methyl-2-oxo- ethyl]carbamate (8.0 g, 34 mmol, 1.0 eq) , the reaction mixture was degassed and purged with N2 for three times, then i-PrMgCl (2 M, 35 mL, 2.0 eq) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at 25 °C for 1 h under N2 atmosphere.
  • reaction mixture was quenched with saturated aqueous NH4Cl (300 mL) and extracted with EtOAc (500 mL, twice). The combined organic layers were washed with saturated aqueous NaCl (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • bor.7 (6-(4-((tert-butoxycarbonyl) alanyl) piperazin-1-yl) pyridin-3-yl) boronic acid
  • Step 1 To a solution of tert-butyl 4-(5-bromo-2-pyridyl) piperazine-1-carboxylate 13.1 (1.0 g, 2.9 mmol, 1.0 eq) in dioxane (0.5 mL) was added HCl/dioxane (2.0 M, 2.0 mL) at 25 °C. The mixture was stirred at 25 °C for 2 h.
  • Step 3 A mixture of tert-butyl N-[2-[4-(5-bromo-2-pyridyl)piperazin-1-yl]-1-methyl- 2-oxo-ethyl]carbamate 13.3 (1.1 g, 2.7 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5- Attorney Docket No.: 185992002240 tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.0 g, 4.0 mmol, 1.5 eq), Pd(dppf)Cl2 (0.20 g, 0.27 mmol, 0.10 eq) and AcOK (0.79 g, 8.0 mmol, 3.0 eq) in dioxane (3.0 mL) was degassed and purged with N2 three times at 25 °C.
  • bor.8 tert-butyl (3-methyl-1-oxo-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) amino) butan-2-yl) carbamate T o a solution of 4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline 14.1 (1.0 g, 4.6 mmol, 1.0 eq) and 2-(tert-butoxycarbonylamino) -3-methyl-butanoic acid (1.0 g, 4.6 mmol, 1.0 eq) in DMF (20 mL) was added HATU (2.6 g, 6.9 mmol, 1.5 eq) and DIEA (2.0 g, 15 mmol, 2.7 mL, 3.4 eq) in turns, then the resulting mixture was stirred at 25 °C for 1 h.
  • bor.9 tert-butyl (1-oxo-1-(4- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2- yl)carbamate
  • Step 1 To a solution of 1-bromo-4-iodo-benzene (0.5 g, 1.77 mmol, 1 eq) and tert- butyl (1-oxopropan-2-yl)carbamate (306.13 mg, 1.77 mmol, 1 eq) in THF (10 mL) was added Attorney Docket No.: 185992002240 i-PrMgCl (1.3 M, 2.72 mL, 2 eq) at 0 °C . The mixture was stirred at 25 °C for 2 hours under N2 atmosphere.
  • reaction mixture was quenched by saturated ammonium chloride aqueous solution (30 mL) at 0°C, and then extracted with ethyl acetate (15 mL, three times). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step 2 To a solution of tert-butyl (1-(4-bromophenyl)-1-hydroxypropan-2- yl)carbamate (0.38 g, 1.15 mmol, 1 eq) in DCM (4 mL) was added (1,1-diacetoxy-3-oxo-1,2- benziodoxol-1-yl) acetate (0.98 g, 2.30 mmol, 713.05 ⁇ L, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was filtered and the filtrate was concentrated to give a residue.
  • bor.11 tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]azetidine-1- carboxylate
  • tert-butyl 3-iodoazetidine-1-carboxylate (1.00 g, 3.53 mmol, 1.00 eq) and K2CO3 (0.98 g, 7.06 mmol, 2.00 eq) in DMF (10.0 mL) was added 4-(4,4,5,5- tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (0.85 g, 3.89 mmol, 1.10 eq) at 20 °C.
  • bor.12 tert-butyl 3-[4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1- carboxylate
  • 4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (1.00 g, 4.54 mmol, 1.00 eq)
  • tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.02 g, 5.45 mmol, 1.20 eq) and PPh 3 (1.79 g, 6.82 mmol, 1.50 eq) in THF (15.0 mL) was added (3E)-3- (dimethylcarbamoylimino)-1,1-dimethyl-urea (1.17 g, 6.82 mmol, 1.50 eq) at 0 °C.
  • bor.13 tert-butyl 3-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- pyridyl]oxymethyl]azetidine-1-carboxylate
  • Step 1 To a solution of 5-bromopyridin-2-ol (1 g, 5.75 mmol, 1 eq), tert-butyl 3- (hydroxymethyl)azetidine-1-carboxylate (1.61 g, 8.62 mmol, 1.5 eq) in THF (10 mL) was added DIAD (1.74 g, 8.62 mmol, 1.67 mL, 1.5 eq) and PPh3 (2.26 g, 8.62 mmol, 1.5 eq) at 0°C.
  • reaction mixture was added into water(10 mL) and extracted with ethyl acetate30 mL (10 mL, three times). The combined organic layers were washed withbrine (10 mL, three times), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step 3 To a solution of [1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl]methanol (600 mg, 2.71 mmol, 1 eq) and TEA (1.65 g, 16.27 mmol, 2.26 mL, 6 eq) in DCM (10 mL) was added methylsulfonyl methanesulfonate (1.42 g, 8.13 mmol, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL *3).
  • Step 5 To a solution of 5-benzyl-1,3,3a,4,6,6a-hexahydrothieno[3,4-c]pyrrole (600 mg, 2.74 mmol, 1 eq) in DCM (10 mL) was added m-CPBA (1.67 g, 8.21 mmol, 85% purity, 3 eq) at 0°C, the mixture was stirred at 25 °C for 16 hours.
  • Step 6 To a solution of Pd/C (37 mg, 10% purity) and Pd(OH)2 (37 mg, 20% purity) inMeOH MeOH (10 mL) was added 5-benzyl-1,3,3a,4,6,6a-hexahydrothieno[3,4-c]pyrrole 2,2-dioxide (370 mg, 1.47 mmol, 1 eq) at 25 °C under N 2 .
  • the suspension was degassed Attorney Docket No.: 185992002240 under vacuum and purged with H 2 three times. The mixture was stirred under H 2 (50 psi) at 50°C for 16 hours.
  • the reaction mixture was diluted with MeOH (10 mL).
  • reaction mixture was diluted with water (50 ml) and then extracted with ethyl acetate(50 mL, three times). The combined organic phase was washed with brine (20 mL, three times), dried with Na2SO4, filtrated and evaporated.
  • Step 2 To a solution of tert-butyl 1-[(4-methoxyphenyl)methyl]-2,3,3a,4,6,6a- hexahydropyrrolo [3,4-b]pyrrole-5-carboxylate (2.8 g, 8.42 mmol, 1 eq) in THF (30 mL) was added H2O (10 mL), I2 (16.03 g, 63.17 mmol, 7.5 eq) and NaHCO3 (7.08 g, 84.23 mmol, 10 eq) at 20°C, the mixture was stirred at 20 °C for12 hours.
  • reaction mixture was diluted with water (20mL) and then extracted with ethyl acetate(30mL, three times), the combined organic phase was washed with brine (10mL, three times) ,dried with Na2SO4, filtrated and evaporated.
  • Step 3 To a solution of tert-butyl1-[(4-methoxyphenyl)methyl]-2-oxo-3a,4,6,6a- tetrahydro-3H- pyrrolo[3,4-b]pyrrole-5-carboxylate (1.1 g, 3.18 mmol, 1 eq) in dioxane (2 mL) was added HCl/dioxane (2.5 M, 15 mL, 11.8 eq) at 20°C. The mixture was stirred at 20 °C for 12 hours.
  • Step 4 To a solution of 1-[(4-methoxyphenyl)methyl]-3,3a,4,5,6,6a- hexahydropyrrolo[3,4-b] pyrrol-2-one (1 g, 3.15 mmol, 1 eq, HCl) in THF (15 mL), H2O (2 mL) were added NaHCO 3 (1.32 g, 15.74 mmol, 5 eq) and Cbz-Cl (800 mg, 4.69 mmol, 1.49 eq) at 20°C. The mixture was stirred at 20°C for 12 hours.
  • reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (30 mL, three times), the combined organic phase was washed with brine (10mL, 3 times), dried with Na 2 SO 4 , filtrated and evaporated.
  • Step 5 To a solution of benzyl1-[(4-methoxyphenyl)methyl]-2-oxo-3a,4,6,6a- tetrahydro-3H-pyrrolo [3,4-b]pyrrole-5-carboxylate (1.2 g, 2.49 mmol, 1 eq) in MeCN (20 mL), H2O (2 mL) was added ceric ammonium nitrate (6.8 g, 12.40 mmol, 6.18 mL, 4.98 eq) at 20°C. The mixture was stirred at 20°C for 12 hours.
  • reaction mixture was diluted with water (10 mL), quenched with saturated sodium sulfite solution (20 mL), and then extracted with ethyl acetate (30mL, three times). The combined organic phase was washed with brine (10 mL, three times), dried with Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 80% tetrahydrofuran/Petroleum ether gradient @ 40 mL/min)to give crude product as a yellow solid.
  • Step 6 To a mixture of benzyl 2-oxo-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrole-5- carboxylate (140 mg, 537.87 ⁇ mol, 1 eq) in MeOH (20 mL) were added Pd/C (186.67 mg, Attorney Docket No.: 185992002240 175.41 ⁇ mol, 10% purity, 0.033 eq) at 20 °C. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (50psi) at 20 °C for 3 hours.
  • amine.11 6-methyl-2,6-diazaspiro[3.5]nonan-5-one
  • Step 1 To a mixture of tert-butyl N-(3-hydroxypropyl)-N-methyl-carbamate (8 g, 42.27 mmol, 1 eq) and PPh3 (14.41 g, 54.95 mmol, 1.3 eq) in DCM (80 mL) was added CBr4 (18.22 g, 54.95 mmol, 1.3 eq) at 0 °C.
  • Step 2 To a solution of tert-butyl 3-(chloromethyl) -3-cyano-pyrrolidine-1- carboxylate (2.5 g, 10.22 mmol, 1 eq) in DMF (25 mL) was added acetylsulfanylpotassium (1.63 g, 14.30 mmol, 1.4 eq) at 20 °C. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was quenched by addition of water (50 mL) at 20 °C, and then extracted with EtOAc (40 mL, 3 times). The combined organic layers were dried over Na2SO4, filtrated and evaporated.
  • the crude product was purified by reversed-phase HPLC (0.1% FA Attorney Docket No.: 185992002240 condition) and lyophilized to give the tert-butyl 5-benzyl-1-oxohexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (1.2 g, 3.79 mmol, 34.74% yield) as a yellow oil.
  • Step 2 To a screw-cap vial equipped with a magnetic stir bar was added tert-butyl N- [5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]carbamate (430 mg, 1.06 mmol, 1 eq) and HCl/dioxane (2 M, 10 mL) sequentially.
  • reaction solution was stirred at 25 °C for 12 hours.
  • the reaction mixture was partitioned between EtOAc (1000 mL) and water (500 mL), washed with brine(400 mL), died over Na2SO4, filtered and evaporated.
  • the crude product was purified by flash silica gel chromatography (ISCO; 330 g SepaFlash Silica Flash Column, Eluent of 0 ⁇ 30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give the tert-butyl N-[2-[(6- bromo-3-pyridyl)oxy]ethyl]-N-methyl-carbamate (6 g, 18.12 mmol, 18.54% yield) as a white solid.
  • ISCO 330 g SepaFlash Silica Flash Column, Eluent of 0 ⁇ 30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min
  • Step 2 To a solution of tert-butyl N-[2-[(6-bromo-3-pyridyl)oxy]ethyl]-N-methyl- carbamate (4.3 g, 12.98 mmol, 1 eq), Pd 2 (dba) 3 (1.2 g, 1.31 mmol, 1.01e-1 eq), PCy 3 (0.75 g, 2.67 mmol, 867.05 ⁇ L, 2.06e-1 eq) and LiCl (2.79 g, 65.93 mmol, 1.35 mL, 5.08 eq) in dioxane (40 mL) was added tributyl(tributylstannyl)stannane (22.03 g, 37.98 mmol, 19.02 mL, 2.93 eq) under N2.
  • the reaction solution was stirred at 110 °C for 12 hours.
  • the reaction solution was extracted with EtOAc (200 mL, 3 times).
  • the combined organic phase was washed with brine (200 mL, 2 times), dried over Na2SO4, filtered and evaporated.
  • the residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 3% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give a residue.
  • Step 3 To a solution of tert-butyl N-methyl-N-[2-[(6-tributylstannyl-3- pyridyl)oxy]ethyl]carbamate (1 g, 1.85 mmol, 1 eq) , 2,4-dichloro-N,N-dimethyl-quinolin-7- amine (600 mg, 2.49 mmol, 1.35 eq) and LiCl (420 mg, 9.91 mmol, 203.09 ⁇ L, 5.36 eq) in m- xylene (20 mL) was added Pd(PPh3)2Cl2 (260 mg, 370.43 ⁇ mol, 2.01e-1 eq) under N2.
  • Step 1 A mixture of 7-bromo-2,4-dichloro-quinoline (500 mg, 1.81 mmol, 1 eq), tert-butyl N-methyl-N-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-2-pyridyl]oxy]ethyl]carbamate (615 mg, 1.63 mmol, 9.01e-1 eq) in S2 (6.6 mL).
  • Step 1 A mixture of 2,4-dichloro-6-fluoro-7-methoxy- quinoline (0.200 g, 0.813 mmol, 1.00 eq) ,tert-butyl N-methyl-N-[2-[methyl-[5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl] amino]ethyl]carbamate (318 mg, 0.813 mmol, 1.00 eq) in S2 (4.5 mL).
  • Step 2 According to Scheme 3 Step 1: A solution of 2,4-dichloroquinolin-7-ol (1.3 g, 6.07 mmol, 1 eq), tert-butyl N-methyl-N-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]ethyl]carbamate (1.46 g, 3.88 mmol, 6.38e-1 eq) in S1 (11 mL).
  • Step 3 To a solution of tert-butyl N-[2-[4-(4-chloro-7-hydroxy-2-quinolyl) phenoxy]ethyl]-N-methyl-carbamate (250 mg, 582.88 ⁇ mol, 1 eq) in MeCN (5 mL) was added iodoethane (130 mg, 833.52 ⁇ mol, 66.67 ⁇ L, 1.43 eq) and K2CO3 (240 mg, 1.74 mmol, 2.98 eq). The reaction mixture was stirred at 60 °C for 12 hours. The residue was partitioned between ethyl acetate (10 mL) and water (20mL).
  • Step 2 According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert- butyl N-[2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (250 mg, 542.39 ⁇ mol, 1 eq), 2,7-diazaspiro[4.5]decan-6-one (100 mg, 648.47 ⁇ mol, 1.2 eq), Attorney Docket No.: 185992002240 Cs 2 CO 3 (530 mg, 1.63 mmol, 3 eq), SPhos Pd G3 (45 mg, 57.67 ⁇ mol, 1.06e-1 eq) in dioxane (5 mL).
  • the reaction mixture was partitioned between EtOAc (100 mL) and water (80 mL), washed with brine(70 mL), died over Na 2 SO 4 , filtered and evaporated under reduced pressure to give the crude product.
  • the crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0 ⁇ 30% EtOAc/PE gradient @ 40 mL/min) to give C.2abb (160 mg, 277.57 ⁇ mol, 49.18% yield, 92.4% purity) as a yellow solid.
  • E.1z (0.41 g, 0.61 mmol, quant.).
  • E.1aa tert-butyl 2-[2-[6-[2-(tert-butoxycarbonylamino) propanoyl]-3-pyridyl]-6-fluoro-7- methoxy-4-quinolyl]-2,7-diazaspiro [4.5] decane-7-carboxylate.
  • TFA To a solution of substrate C.2 or D.1 or E.1 (1.0 eq) in DCM (0.15M) was added TFA (> 10 eq) at 25 °C. After stirring at 25 °C for 4 h, the reaction mixture was filtered and concentrated under reduced pressure. Purifications described below.
  • C onditions 3 TMSOTf To a solution of substrate C.2 or D.1 or E.1 (1.0 eq) in DCM (0.15M) was added TMSOTf (> 3 eq) and 2,6-dimethylpyridine (>9 eq) at 0°C. After stirring at 0°C for 0.5 hours, the reaction mixture was concentrated under reduced pressure to give a residue at 25°C.
  • Example 1 1-(4-(5-(6,7-dimethoxy-4-(pyrrolidin-1-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one
  • Step 5 Conditions 3 SNAr with substrate A.5i (0.10 g, 0.23 mmol, 1.0 eq). After work-up the crude product was triturated with MeOH (10 mL) at 25 °C for 20 min to give Example 1 (32 mg, 68 ⁇ mol, 29% yield, 99% purity) as an off-white solid.
  • Example 2 (1-(2-(6-(azetidin-1-yl) pyridin-3-yl)-6-fluoro-7-methoxyquinolin-4-yl) pyrrolidin-3-yl) methanol
  • Step 5 Conditions 4 Buchwald with substrate A.5b (0.10 mg, 0.29 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 7 (gradient: 30%-50% over 8 min) to give Example 2 (84 mg, 0.21 mmol, 71% yield, 100% Attorney Docket No.: 185992002240 purity), which was obtained as an off-white solid.
  • Example 3 39 mg, 80 ⁇ mol, 42% yield, 98% purity
  • Example 4 (1.9 mg, 4.5 ⁇ mol, 5.7% yield, 100% purity) as a yellow solid.
  • Example 5 22 mg, 52 ⁇ mol, 15% yield, 100% purity
  • Example 6 (7 mg, 16.77 ⁇ mol, 5.26% yield, 100% purity) as a white solid.
  • Example 8 2-(4-(5-(6,7-dimethoxy-4-(pyrrolidin-1-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-ol
  • Step 3 Conditions 1 HCl with substrate C.2f (70 mg, 0.12 mmol, 1.0 eq). The reaction mixture was concentrated under reduced pressure to give a crude product purified with SCX (see general protocol).
  • Example 8 (40 mg, 86 ⁇ mol, 86% yield, 99% purity) was obtained as a yellow solid.
  • Example 10 (47 mg, 0.11 mmol, 57% yield, 98% purity) was obtained as an off-white solid.
  • Example 12 4-(2-methylpyrrolidin-1-yl)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline A ccording to Scheme 3 Step 3: Conditions 2 TFA with subtrate C.2o (0.16 mg, 0.33 mmol, 1.0 eq), TFA (26 eq). After work-up the reaction mixture was concentrated and purified by prep-HPLC 6 to give after lyophilization Example 12 (0.13 g, 0.35 mmol, quant.) as a yellow fluffy powder.
  • Example 14 (33 mg, 77 ⁇ mol, 12% yield, 99% purity) as a white solid.
  • Example 19 was further purified with SCX (see general protocol).
  • Example 27 6-fluoro-N, N-dimethyl-2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-7-amine
  • Step 2 Conditions 1 HCl with substrate E.6f (0.15 g, 0.17 mmol, 1.0 eq). After work-up the residue was first purified by prep-HPLC 8 (gradient: 0%- 30% over 9 min) and then basified with SCX (see general protocol) to give Example 27 (23 mg, 46 ⁇ mol, 26% yield, 98% purity) as a yellow solid.
  • Example 30 (10 mg, 0.02 mmol, 34% yield, 98% purity, HCl) as a yellow solid.
  • Example 31 2-amino-1-(5-(6-fluoro-4-(3-(hydroxymethyl) pyrrolidin-1-yl)-7- methoxyquinolin-2-yl) pyridin-2-yl) propan-1-one
  • Step 3 Conditions 1 HCl with substrate C.2d (0.16 g, 0.31 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 5%-35% over 9 min). The eluent was lyophilized to give Example 31 (21 mg, 48 ⁇ mol, 16% yield, 96% purity) as a yellow gum.
  • the residual aqueous solution was lyophilized to give 2-[2-[6-(azetidin-1- yl) -3-pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-2, 9-diazaspiro [4.5] decane as a white solid.
  • Example 32 (12 mg, 27 ⁇ mol, 15% yield, 98% purity), which was obtained as a white solid.

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Abstract

Provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R1, R2, Ring A, L, R6, R7, R8, R9, and R10 are as defined elsewhere herein. Also provided are methods of preparing compounds of formula (I). Also provided herein are methods of modulating TDP-43 and methods of treating a disease or condition mediated by TDP-43 in an individual in need thereof.

Description

Attorney Docket No.: 185992002240 AMINO QUINOLINE COMPOUNDS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority benefit of United States Provisional Patent Application No. 63/618,189 filed January 5, 2024, which is hereby incorporated herein by reference in its entirety. FIELD OF THE INVENTION Aspects of the invention generally relate to amino quinoline compounds, pharmaceutical compositions, kits comprising the same, their use as biomolecular condensate modifying drugs (c-mods), and their use in the treatment of a disease or condition. BACKGROUND OF THE INVENTION TAR DNA-binding protein 43 (TDP-43) is a highly conserved and ubiquitously- expressed RNA/DNA-binding protein involved in RNA processing. Cytoplasmic aggregates of TDP-43 occur in >97% of amyotrophic lateral sclerosis (ALS) cases. Stress-induced formation of cytoplasmic TDP-43 biological condensates represent an intermediate, reversible, pre-pathological state in neurons. Over time, TDP-43-containing condensates lose their fluid-like properties and potentially convert into irreversible, toxic aggregates [Ling, et al., Neuron 79, 416–438 (2013); Markmiller, et al. Cell Reports 36, 109685 (2021); and Lu et al. Nat Cell Biol 1–16 (2022)]. The role of condensate dysfunction in ALS pathogenesis is supported by the discovery of condensate genes as genetic modifiers of ALS (e.g., TAF15, EWSR1, TIA1, HNRNPA1, HNRNPA2B1), as well as co-localization of C9ORF72 ALS G4C2 expansion- derived dipeptide repeats (DPRs) and stress granule proteins with TDP-43 inclusions in preclinical models. Nuclear depletion of TDP-43 into cytoplasmic condensates leads to toxic loss of splicing function in motor neurons. Small molecule condensate modifying drugs (c- mods) that directly modulate TDP-43 condensates can treat diverse forms of ALS. [Chew, J. et al., Mol. Neurodegener. 14, 9 (2019); and Taylor, J. P., et al., Nature 539, 197–206 (2016)]. Attorney Docket No.: 185992002240 BRIEF SUMMARY OF THE INVENTION In one aspect, provided herein is a compound of formula (I)
Figure imgf000004_0001
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R1 and R2 are each independently C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl wherein the C1-6alkyl of R1 or R2 is optionally substituted with one or more R1a, the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1 or R2 is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), -S(=O)2R14, -S(=O)2N(R13)(R14), or C3-8cycloalkyl group of R 1 or R2 are taken together with the atoms to which they are attached to form a C3- 8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1b; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl, wherein the 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl of R1 and R2 is optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R 13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - Attorney Docket No.: 185992002240 N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R3 is optionally substituted with one or more R3a, and optionally, two substituents of R3 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl is optionally substituted one or more R3b; Ring A is 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 12-membered unsaturated heterocyclyl or 5- to 10-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R4 is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4 is optionally substituted with one or more R4b, and the 3- to 8-membered heterocyclyl of R4 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-, wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)- is optionally substituted by one or more RL; each RL is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - Attorney Docket No.: 185992002240 OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RL are taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R5 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R14, -S(=O)2R14, -S(=O)2N(R13)(R14), or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, or -S(=O)2N(R13)(R14), and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -O-(3- to 12-membered N- containing heterocyclyl), -O-(5- to 6-membered N-containing heteroaryl), -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R6 is optionally substituted by one or more R6a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10- membered heteroaryl, -O-(3- to 12-membered N-containing heterocyclyl), or -O-(5- to 6-membered N-containing heteroaryl) of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14, and the 3- to 8-membered heterocyclyl of R6 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R6 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R6b; Attorney Docket No.: 185992002240 R7, R8, R9, and R10 are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - OR11, -OR12, -SR12, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, - N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, - S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, - S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R7, R8, R9, or R10 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R7, R8, R9, or R10 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R7, R8, R9, or R10 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R7, R8, R9, or R10 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R7b; each R1a, R3a, R4a, R6a, or R7a is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, - CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, - OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, - C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, - S(=O)R14, -S(=O)2R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, - S(=NR15)OR14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R3a, R4a, R6a, or R7a is optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R3a, R4a, R6a, or R7a comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, -N(Rx)(Ry), oxo, - CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein Attorney Docket No.: 185992002240 the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; each R11 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R11 is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry), and the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R11 is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 12-membered heterocyclyl; each R12 is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R12 is optionally substituted with one or more halo, deuterium, C1-6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R13 is independently H, C1-6alkyl, or C3-8cycloalkyl; each R14 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, - N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl is optionally substituted by -OH, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, -OH, or -N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl). Attorney Docket No.: 185992002240 In some embodiments, the compound of formula (I) is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Any embodiments provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, apply where applicable to any other formula detailed herein, the same as if each and every embodiment were specifically and individually listed. Thus, it is understood and described that each embodiment provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, such as embodiments related to R1, R2, R3, Ring A, R4, L, R5, R6, R7, R8, R9, R10, R1a, R3a, R6a, R7a, R1b, R3b, R4b, R5b, R6b, R7b, R11, R12, R13, R14, R15, Rx, and Ry, apply to formula (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the same as if each and every embodiment were specifically and individually listed. It is also understood and described that all such embodiments may be used in any of the pharmaceutical compositions, methods, kits, uses, or other aspects detailed herein. In one aspect, provided is a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients. This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III- A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In another variation, provided is a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided is a method for treating a disease or condition mediated by TDP-43, comprising administering to an individual in need thereof a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a Attorney Docket No.: 185992002240 pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients. This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In another variation, provided is a method for treating a disease or condition mediated by TDP-43, comprising administering to an individual in need thereof a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided herein is a method of modulating TDP-43, comprising contacting a cell with an effective amount of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In another variation, provided herein is a method of modulating TDP- 43, comprising contacting a cell with an effective amount of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided herein is a method of modulating TDP-43 target gene expression levels, comprising contacting a cell with an effective amount of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. This aspect in some embodiments may employ a Attorney Docket No.: 185992002240 compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III- A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In another variation, provided herein is a method of modulating TDP-43 target gene expression levels, comprising contacting a cell with an effective amount of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in the treatment of a disease or condition mediated by TDP-43. This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In another variation, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in the treatment of a disease or condition mediated by TDP-43. This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided herein is the use of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients, in the manufacture a medicament for the treatment of Attorney Docket No.: 185992002240 a disease or condition mediated by TDP-43. This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III- A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In another variation, provided herein is the use of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients, in the manufacture a medicament for the treatment of a disease or condition mediated by TDP-43. This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided herein is a kit, comprising (i) a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and (ii) instructions for use in treating a TDP-43 mediated disease or condition in an individual in need thereof. This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III- A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In another variation, provided herein is a kit, comprising (i) a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating a TDP-43 mediated disease or condition in an individual in need thereof. This aspect in some embodiments may employ a compound of any of formulas (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. All pharmaceutical compositions, methods, kits, uses, or other aspects described herein with reference to formula (I), or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, are also hereby described and embraced for any one of the other formulas detailed herein such as formula (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), the same as if each and every embodiment were specifically and individually listed. Attorney Docket No.: 185992002240 DETAILED DESCRIPTION OF THE INVENTION “Individual” refers to mammals and includes humans and non-human mammals. Examples of individuals include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, individual refers to a human. As used herein, “about” a parameter or value includes and describes that parameter or value per se. For example, “about X” includes and describes X per se. “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results may include one or more of the following: decreasing one or more symptom resulting from the disease or condition; diminishing the extent of the disease or condition; slowing or arresting the development of one or more symptom associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition); and relieving the disease, such as by causing the regression of clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival). As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition. As used herein, the term “therapeutically effective amount” or “effective amount” intends such amount of a compound of the disclosure or a pharmaceutically salt thereof sufficient to effect treatment when administered to an individual. As is understood in the art, an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient, or compound, which may be in a pharmaceutically acceptable carrier. Attorney Docket No.: 185992002240 As used herein, by “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects. The term “alkyl”, as used herein, refers to an unbranched or branched saturated univalent hydrocarbon chain. As used herein, alkyl has 1-20 carbons (i.e., C1-20alkyl), 1-16 carbons (i.e., C1-16alkyl), 1-12 carbons (i.e., C1-12alkyl), 1-10 carbons (i.e., C1-10alkyl), 1-8 carbons (i.e., C1-8alkyl), 1-6 carbons (i.e., C1-6alkyl), 1-4 carbons (i.e., C1-4alkyl), or 1-3 carbons (i.e., C1-3alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, iso-pentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “butyl” includes n-butyl, sec-butyl, iso-butyl, and tert-butyl; and “propyl” includes n-propyl and iso- propyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkyl” group, may be referred to as an “alkylene”. The term “alkenyl”, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon double bond. As used herein, alkenyl has 2-20 carbons (i.e., C2-20alkenyl), 2-16 carbons (i.e., C2-16alkenyl), 2-12 carbons (i.e., C2-12alkenyl), 2-10 carbons (i.e., C2-10alkenyl), 2-8 carbons (i.e., C2-8alkenyl), 2-6 carbons (i.e., C2-6alkenyl), 2-4 carbons (i.e., C2-4alkenyl), or 2-3 carbons (i.e., C2-3alkenyl). Examples of alkenyl include, but are not limited to, ethenyl, prop-1-enyl, prop-2-enyl 1,2- butadienyl, and 1,3-butadienyl. When an alkenyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propenyl” includes prop-1- enyl and prop-2-enyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkenyl” group, may be referred to as an “alkenylene”. The term “alkynyl”, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon triple bond. As used herein, alkynyl has 2-20 carbons (i.e., C2-20alkynyl), 2-16 carbons (i.e., C2-16alkynyl), 2-12 carbons (i.e., C2-12alkynyl), 2-10 carbons (i.e., C2-10alkynyl), 2-8 carbons (i.e., C2-8alkynyl), 2-6 carbons (i.e., C2-6alkynyl), 2-4 carbons (i.e., C2-4alkynyl), or 2-3 carbons (i.e., C2-3alkynyl). Attorney Docket No.: 185992002240 Examples of alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1- ynyl, but-2-ynyl, and but-3-ynyl. When an alkynyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propynyl” includes prop-1- ynyl and prop-2-ynyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkynyl” group, may be referred to as an “alkynylene”. The term “alkoxy”, as used herein, refers to an -O-alkyl moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. The term “aryl”, as used herein, refers to a fully unsaturated carbocyclic ring moiety. The term “aryl” encompasses monocyclic and polycyclic fused-ring moieties. As used herein, aryl encompasses ring moieties comprising, for example, 6 to 20 annular carbon atoms (i.e., 6- to 20-membered aryl), 6 to 16 annular carbon atoms (i.e., 6- to 16-membered aryl), 6 to 12 annular carbon atoms (i.e., 6- to 12-membered aryl), or 6 to 10 annular carbon atoms (i.e., 6- to 10-membered aryl). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl. The term “cycloalkyl”, as used herein, refers to a saturated or partially unsaturated carbocyclic ring moiety. The term “cycloalkyl” encompasses monocyclic and polycyclic ring moieties, wherein the polycyclic moieties may be fused, branched, or spiro. Cycloalkyl includes cycloalkenyl groups, wherein the ring moiety comprises at least one annular double bond. Cycloalkyl includes any polycyclic carbocyclic ring moiety comprising at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, cycloalkyl includes rings comprising, for example, 3 to 20 annular carbon atoms (i.e., a C3-20cycloalkyl), 3 to 16 annular carbon atoms (i.e., a C3-16cycloalkyl), 3 to 12 annular carbon atoms (i.e., a C3-12cycloalkyl), 3 to 10 annular carbon atoms (i.e., a C3-10cycloalkyl), 3 to 8 annular carbon atoms (i.e., a C3-8cycloalkyl), 3 to 6 annular carbon atoms (i.e., a C3- 6cycloalkyl), or 3 to 5 annular carbon atoms (i.e., a C3-5cycloalkyl). Monocyclic cycloalkyl ring moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbonyl, decalinyl, 7,7-dimethyl -bicyclo [2.2.1]heptanyl, and the like. Still further, cycloalkyl also includes spiro cycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5]undecanyl. Attorney Docket No.: 185992002240 The term “halo”, as used herein, refers to atoms occupying groups VIIA of The Periodic Table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo). Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-4haloalkyl” is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like. The term “heteroaryl”, as used herein, refers to an aromatic (fully unsaturated) ring moiety that comprises one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heteroaryl” includes both monocyclic and polycyclic fused-ring moieties. As used herein, a heteroaryl comprises, for example, 5 to 20 annular atoms (i.e., a 5- to 20-membered heteroaryl), 5 to 16 annular atoms (i.e., a 5- to 16-membered heteroaryl), 5 to 12 annular atoms (i.e., a 5- to 12-membered heteroaryl), 5 to 10 annular atoms (i.e., a 5- to 10-membered heteroaryl), 5 to 8 annular atoms (i.e., a 5- to 8-membered heteroaryl), or 5 to 6 annular atoms (i.e., a 5- to 6-membered heteroaryl). Any monocyclic or polycyclic aromatic ring moiety comprising one or more annular heteroatoms is considered a heteroaryl, regardless of the point of attachment to the remainder of the molecule (i.e., the heteroaryl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heteroaryl moiety). Examples of heteroaryl groups include, but are not limited to, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and pyridazinyl. The term “heterocyclyl”, as used herein, refers to a saturated or partially unsaturated cyclic moiety that encompasses one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes both monocyclic and polycyclic ring moieties, wherein the polycyclic ring moieties may be fused, bridged, or spiro. Any non-aromatic monocyclic or polycyclic ring moiety comprising at least one annular heteroatom is considered a heterocyclyl, regardless of the point of attachment to the remainder of the molecule (i.e., the heterocyclyl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heterocyclyl moiety). Further, the term heterocyclyl is intended to encompass any polycyclic ring moiety comprising at least one annular heteroatom wherein the polycyclic ring moiety comprises at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, a heterocyclyl comprises, for example, 3 to 20 annular atoms (i.e., a 3- to 20-membered heterocyclyl), 3 to 16 annular atoms (i.e., a 3- to 16- membered heterocyclyl), 3 to 12 annular atoms (i.e., a 3- to 12-membered heterocyclyl), 3 to 10 annular atoms (i.e., a 3- to 10-membered heterocyclyl), 3 to 8 annular atoms (i.e., a 3- to Attorney Docket No.: 185992002240 8-membered heterocyclyl), 3 to 6 annular atoms (i.e., a 3-6 membered heterocyclyl), 3 to 5 annular atoms (i.e., a 3- to 5-membered heterocyclyl), 5 to 8 annular atoms (i.e., a 5- to 8- membered heterocyclyl), or 5 to 6 annular atoms (i.e., a 5- to 6-membered heterocyclyl). Examples of heterocyclyl groups include, e.g., azetidinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, or tetrahydropyranyl. Examples of spiro heterocyclyl rings include, but are not limited to, bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1- azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinyl, 5,7- dihydrofuro[3,4-d]pyrimidinyl, and 5,7-dihydrothieno[3,4-d]pyrimidinyl, where the heterocyclyl can be bound via either ring of the fused system. The term “oxo”, as used herein, refers to a =O moiety. The terms “spiro”, “spirocycle” and “spirocyclic”, as used herein, refer to a polycyclic moiety in which two of the rings share one atom in common. The terms “spiro”, “spirocycle” and “spirocyclic” may refer to a saturated or partially unsaturated carbocycle, or a saturated or partially unsaturated heterocycle. The term “fused”, as used herein, refers to a polycyclic moiety in which two of the rings share two adjacent atoms in common. The term “fused” may refer to a saturated or partially unsaturated carbocycle, or a saturated or partially unsaturated heterocycle. The term “bridged”, as used herein, refers to a polycyclic moiety in which two of the rings share three or more atoms in common, and the bridgehead atoms are separated by at least one atoms. The term “bridged” may refer to a saturated or partially unsaturated carbocycle, or a saturated or partially unsaturated heterocycle. The terms “optional” and “optionally”, as used herein, mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not. Accordingly, the term “optionally substituted” infers that any one or more (e.g., 1, 2, 1 to 5, 1 to 3, 1 to 2, etc.) hydrogen atoms on the designated atom or moiety or group may be replaced or not replaced by an atom or moiety or group other than hydrogen. By way of illustration and not limitation, the phrase “methyl optionally substituted with one or more chloro” encompasses -CH3, -CH2Cl, -CHCl2, and -CCl3 moieties. It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments. Attorney Docket No.: 185992002240 The term “pharmaceutically acceptable salt”, as used herein, of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), which is incorporated herein by reference in its entirety. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, trifluoroacetic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N- ethylpiperidine, and the like. Isotopically labeled forms of the compounds depicted herein may be prepared. Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. In some Attorney Docket No.: 185992002240 embodiments, a compound of formula (I) is provided wherein one or more hydrogen is replaced by deuterium or tritium. Some of the compounds provided herein may exist as tautomers. Tautomers are in equilibrium with one another. By way of illustration, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds of this disclosure are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, for example, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, imidic-acid containing compounds are understood to include their amide tautomers. Also provided herein are prodrugs of the compounds depicted herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, provided herein are prodrugs of the compounds depicted herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof. Prodrugs are compounds that may be administered to an individual and release, in vivo, a compound depicted herein as the parent drug compound. It is understood that prodrugs may be prepared by modifying a functional group on a parent drug compound in such a way that the modification is cleaved in vitro or in vivo to release the parent drug compound. See, e.g., Rautio, J., Kumpulainen, H., Heimbach, T. et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov 7, 255–270 (2008), which is incorporated herein by reference in its entirety. The compounds of the present disclosure, or their pharmaceutically acceptable salts, hydrates, or solvates may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- (or as (D)- or (L)- for amino acids). The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms and mixtures thereof in any ratio. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, for example, chromatography and/or fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC), and chiral supercritical fluid chromatography (SFC). When the compounds described herein contain olefinic double bonds or other centers Attorney Docket No.: 185992002240 of geometric asymmetry, unless specified otherwise, it is intended that the present disclosure includes both E and Z geometric isomers. Likewise, cis- and trans- are used in their conventional sense to describe relative spatial relationships. A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose structures are non-superimposable mirror images of one another. “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other. Where enantiomeric and/or diastereomeric forms exist of a given structure, flat bonds indicate a mixture of stereoisomeric forms of the depicted structure may be present, e.g.,
Figure imgf000020_0001
the composition is made up of at least 90%, by weight, dashes or wedges with or without the presence of an “(S)” or “(R)” designation indicate a single enantiomer or diastereomer with known relative or absolute stereochemistry, e.g.,
Figure imgf000020_0002
. COMPOUNDS In one aspect, provided herein is a compound of formula (I)
Figure imgf000020_0003
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein Attorney Docket No.: 185992002240 R1 and R2 are each independently C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl wherein the C1-6alkyl of R1 or R2 is optionally substituted with one or more R1a, the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1 or R2 is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), -S(=O)2R14, -S(=O)2N(R13)(R14), or C3-8cycloalkyl group of R1 or R2 are taken together with the atoms to which they are attached to form a C3- 8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1b; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl of R1 and R2 is optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R3 is optionally substituted with one or more R3a, and optionally, two substituents of R3 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl is optionally substituted one or more R3b; Attorney Docket No.: 185992002240 Ring A is 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 12-membered unsaturated heterocyclyl or 5- to 10-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R4 is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4 is optionally substituted with one or more R4b, and the 3- to 8-membered heterocyclyl of R4 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-, wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)- is optionally substituted by one or more RL; each RL is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RL are taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R5 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R14, -S(=O)2R14, -S(=O)2N(R13)(R14), or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - Attorney Docket No.: 185992002240 N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, or -S(=O)2N(R13)(R14), and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -O-(3- to 12-membered N- containing heterocyclyl), -O-(5- to 6-membered N-containing heteroaryl), -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R6 is optionally substituted by one or more R6a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10- membered heteroaryl, -O-(3- to 12-membered N-containing heterocyclyl), or -O-(5- to 6-membered N-containing heteroaryl) of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14, and the 3- to 8-membered heterocyclyl of R6 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R6 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R6b; R7, R8, R9, and R10 are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - OR11, -OR12, -SR12, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, - N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, - S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, - S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R7, R8, R9, or R10 is optionally substituted by one or more R7a, Attorney Docket No.: 185992002240 the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R7, R8, R9, or R10 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R7, R8, R9, or R10 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R7, R8, R9, or R10 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R7b; each R1a, R3a, R4a, R6a, or R7a is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, - CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, - OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, - C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, - S(=O)R14, -S(=O)2R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, - S(=NR15)OR14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R3a, R4a, R6a, or R7a is optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R3a, R4a, R6a, or R7a comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, -N(Rx)(Ry), oxo, - CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; each R11 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R11 is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry), and Attorney Docket No.: 185992002240 the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R11 is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 12-membered heterocyclyl; each R12 is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R 12 is optionally substituted with one or more halo, deuterium, C1-6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R13 is independently H, C1-6alkyl, or C3-8cycloalkyl; each R14 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, - N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl is optionally substituted by -OH, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, -OH, or -N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl). In some embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of formula (I), R1 and R2 are each independently C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl wherein the C1-6alkyl of R1 or R2 is optionally substituted with one or more R1a, Attorney Docket No.: 185992002240 the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1 or R2 is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), -S(=O)2R14, -S(=O)2N(R13)(R14), or C3-8cycloalkyl group of R1 or R2 are taken together with the atoms to which they are attached to form a C3- 8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1b; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl of R1 and R2 is optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R3 is optionally substituted with one or more R3a, and optionally, two substituents of R3 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl is optionally substituted one or more R3b; Ring A is 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of Ring A is optionally substituted by one or more R4, and Attorney Docket No.: 185992002240 the 4- to 12-membered unsaturated heterocyclyl or 5- to 10-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R4 is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4 is optionally substituted with one or more R4b, and the 3- to 8-membered heterocyclyl of R4 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-, wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)- is optionally substituted by one or more RL; each RL is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RL are taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R5 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R14, -S(=O)2R14, -S(=O)2N(R13)(R14), or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, or -S(=O)2N(R13)(R14), and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -O-(3- to 12-membered N- containing heterocyclyl), -O-(5- to 6-membered N-containing heteroaryl), -SR12, -SF5, - Attorney Docket No.: 185992002240 N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R6 is optionally substituted by one or more R6a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10- membered heteroaryl, -O-(3- to 12-membered N-containing heterocyclyl), or -O-(5- to 6-membered N-containing heteroaryl) of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14, and the 3- to 8-membered heterocyclyl of R6 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R6 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R6b; R7, R8, R9, and R10 are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - OR11, -OR12, -SR12, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, - N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, - S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, - S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R7, R8, R9, or R10 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R7, R8, R9, or R10 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R7, R8, R9, or R10 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and Attorney Docket No.: 185992002240 optionally, two substituents of R7, R8, R9, or R10 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R7b; each R1a, R3a, R4a, R6a, or R7a is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, - CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, - OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, - C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, - S(=O)R14, -S(=O)2R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, - S(=NR15)OR14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R3a, R4a, R6a, or R7a is optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R3a, R4a, R6a, or R7a comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, -N(Rx)(Ry), oxo, - CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; each R11 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R11 is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry), and the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R11 is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 12-membered heterocyclyl; each R12 is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, Attorney Docket No.: 185992002240 wherein the C1-6alkyl of R12 is optionally substituted with one or more halo, deuterium, C1-6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R13 is independently H, C1-6alkyl, or C3-8cycloalkyl; each R14 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, - N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl is optionally substituted by -OH, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, -OH, or -N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl) , wherein (i) when Ring A is phenyl and R6 is selected from the group consisting of -NH2, -NHCH3, and -N(CH3)3, R1 and R2 are not both C1-2alkyl; (ii) when R1 and R2 are taken together with the N to which they are attached to form a 4- methylpiperazinyl, -(Ring A)-X-L-R6 is not
Figure imgf000030_0001
(iii) when R1 and R2 are taken together with the N to which they are attached to form a morpholinyl, R6 is not selected from the group consisting of -NH2, -NHC(O)CH3, and - NHC(O)O-C(CH3)3; and (iv) when Ring A is pyridin-4yl substituted with -NHC(CH3)phenyl, R1 and R2 are not taken together with the N to which they are attached to form an optionally substituted 2,5- diazabicyclo[2.2.2]octanyl. Attorney Docket No.: 185992002240 In some embodiments of formula (I), R1 and R2 are each independently C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl wherein the C1-6alkyl of R1 or R2 is optionally substituted with one or more R1a, the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1 or R2 is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), -S(=O)2R14, -S(=O)2N(R13)(R14), or C3-8cycloalkyl group of R 1 or R2 are taken together with the atoms to which they are attached to form a C3- 8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1b; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl of R1 and R2 is optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R 13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R 14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R3 is optionally substituted with one or more R3a, and optionally, two substituents of R3 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl is optionally substituted one or more R3b; Attorney Docket No.: 185992002240 Ring A is 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 12-membered unsaturated heterocyclyl or 5- to 10-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R4 is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4 is optionally substituted with one or more R4b, and the 3- to 8-membered heterocyclyl of R4 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-, wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)- is optionally substituted by one or more RL; each RL is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RL are taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R5 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R14, -S(=O)2R14, -S(=O)2N(R13)(R14), or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - Attorney Docket No.: 185992002240 N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, or -S(=O)2N(R13)(R14), and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -SR12, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, - OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, - C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, - S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, - S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R6 is optionally substituted by one or more R6a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R6 is optionally substituted with one or more R6b, - C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14, and the 3- to 8-membered heterocyclyl of R6 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R6 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R6b; R7, R8, R9, and R10 are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - OR11, -OR12, -SR12, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, - N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, - S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, - S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R7, R8, R9, or R10 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R7, R8, R9, or R10 is optionally substituted with one or more R7b, and Attorney Docket No.: 185992002240 the 3- to 8-membered heterocyclyl of R7, R8, R9, or R10 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R7, R8, R9, or R10 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R7b; each R1a, R3a, R4a, R6a, or R7a is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, - CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, - OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, - C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, - S(=O)R14, -S(=O)2R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, - S(=NR15)OR14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R3a, R4a, R6a, or R7a is optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R3a, R4a, R6a, or R7a comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, -N(Rx)(Ry), oxo, - CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; each R11 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R11 is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry), and the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R11 is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 12-membered heterocyclyl; Attorney Docket No.: 185992002240 each R12 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, C1- 6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R13 is independently H, C1-6alkyl, or C3-8cycloalkyl; each R14 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, - N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl is optionally substituted by -OH, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1- 6alkyl, -OH, or -N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with - O(C=O)C1-8alkyl), wherein (i) when Ring A is phenyl and R6 is selected from the group consisting of -NH2, -NHCH3, and -N(CH3)3, R1 and R2 are not both C1-2alkyl; (ii) when R1 and R2 are taken together with the N to which they are attached to form a 4- methylpiperazinyl, -(Ring A)-X-L-R6 is not
Figure imgf000035_0001
(iii) when R1 and R2 are taken together with the N to which they are attached to form a morpholinyl, R6 is not selected from the group consisting of -NH2, -NHC(O)CH3, and - NHC(O)O-C(CH3)3; and Attorney Docket No.: 185992002240 (iv) when Ring A is pyridin-4yl substituted with -NHC(CH3)phenyl, R1 and R2 are not taken together with the N to which they are attached to form an optionally substituted 2,5- diazabicyclo[2.2.2]octanyl. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or salt of any of the foregoing, R1 and R2 are each independently C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), or C3-8cycloalkyl, wherein the C1-6alkyl of R1 or R2 is optionally substituted with one or more R1a, the C3-8cycloalkyl of R1 or R2 is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), or C3-8cycloalkyl group of R 1 or R2 are taken together with the atoms to which they are attached to form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1b; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R 13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R14, - S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R3 is optionally substituted with one or more R3a, and optionally, two substituents of R3 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl is optionally substituted one or more R3b; Attorney Docket No.: 185992002240 Ring A is 4- to 8-membered monocyclic cycloalkenyl, 4- to 8-membered unsaturated monocyclic heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 8-membered monocyclic cycloalkenyl, 4- to 8-membered unsaturated monocyclic heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 8-membered unsaturated monocyclic heterocyclyl or 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R14, - S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R4 is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4 is optionally substituted with one or more R4b, and the 3- to 8-membered heterocyclyl of R4 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-, wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)- is optionally substituted by one or more RL; each RL is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RL are taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R5 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R14, -S(=O)2R14, -S(=O)2N(R13)(R14), or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - Attorney Docket No.: 185992002240 C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R14, or - S(=O)2N(R13)(R14), and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R13)(R14), -C(=NR15)N(R13)R14, - N(R13)S(=O)2R14, -S(=O)N(R13)R14, -S(=O)2N(R13)(R14), or 3- to 12-membered N-containing heterocyclyl, wherein the 3- to 12-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14,and the 3- to 12-membered N-containing heterocyclyl of R6 further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; R7, R8, R9, and R10 are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - OR11, -OR12, -SR12, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, - N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, - S(=O)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R7, R8, R9, or R10 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R7, R8, R9, or R10 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R7, R8, R9, or R10 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R7, R8, R9, or R10 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R7b; each R1a, R3a, R4a, R6a, or R7a is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, - CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, - OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, - C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, - Attorney Docket No.: 185992002240 S(=O)R14, -S(=O)2R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R3a, R4a, R6a, or R7a is optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R3a, R4a, R6a, or R7a comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, -N(Rx)(Ry), oxo, - CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; each R11 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R11 is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry), and the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R11 is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 12-membered heterocyclyl; each R12 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, C1- 6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R13 is independently H, C1-6alkyl, or C3-8cycloalkyl; each R14 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by halo, -OH, -O(C1-6alkyl), -O(C=O)C1- 8alkyl), -N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, and Attorney Docket No.: 185992002240 the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, or - N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl); wherein (i) when Ring A is phenyl and R6 is selected from the group consisting of -NH2, -NHCH3, and -N(CH3)3, R1 and R2 are not both C1-2alkyl; (ii) when R1 and R2 are taken together with the N to which they are attached to form a 4- methylpiperazinyl, -(Ring A)-X-L-R6 is not
Figure imgf000040_0001
(iii) when R1 and R2 are taken together with the N to which they are attached to form a morpholinyl, R6 is not selected from the group consisting of -NH2, -NHC(O)CH3, and - NHC(O)O-C(CH3)3; and (iv) when Ring A is pyridin-4yl substituted with -NHC(CH3)phenyl, R1 and R2 are not taken together with the N to which they are attached to form an optionally substituted 2,5- diazabicyclo[2.2.2]octanyl. In some embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or salt of any of the foregoing, R1 and R2 are each independently C1-6alkyl, C2-6alkenyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R1 or R2 is optionally substituted with one or more R1a, the C3-8cycloalkyl of R1 or R2 is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, or C3-8cycloalkyl group of R1 or R2 are taken together with the atoms to which they are attached to form a C3- Attorney Docket No.: 185992002240 8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1b; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R14, - S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R3 is optionally substituted with one or more R3a, and optionally, two substituents of R3 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl is optionally substituted one or more R3b; Ring A is 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 12-membered unsaturated heterocyclyl or 5- to 10-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R14, - Attorney Docket No.: 185992002240 S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R4 is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4 is optionally substituted with one or more R4b, and the 3- to 8-membered heterocyclyl of R4 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-, wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)- is optionally substituted by one or more RL; each RL is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RL are taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R5 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R14, or - S(=O)2N(R13)(R14), and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R13)(R14), -C(=NR15)N(R13)R14, - N(R13)S(=O)2R14, -S(=O)N(R13)R14, -S(=O)2N(R13)(R14), or 3- to 12-membered N-containing heterocyclyl, wherein the 3- to 12-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14, and the 3- to 12-membered N-containing heterocyclyl of R6 further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; R7, R8, R9, and R10 are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - OR11, -OR12, -SR12, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, - Attorney Docket No.: 185992002240 N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, -S(=O)R14, -S(=O)2R14, - S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R7, R8, R9, or R10 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R7, R8, R9, or R10 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R7, R8, R9, or R10 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R7, R8, R9, or R10 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R7b; each R1a, R3a, R6a, or R7a is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, -CN, - N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, - OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, - C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, - S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R3a, R6a, or R7a is optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R3a, R6a, or R7a comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, -N(Rx)(Ry), oxo, - CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; Attorney Docket No.: 185992002240 each R11 is independently H, C1-6alkyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C1-6alkyl of R11 is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry) , and the phenyl or 5- to 6-membered heteroaryl of R11 is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R12 is independently H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, C1- 6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R13 is independently H, C1-6alkyl, or C3-8cycloalkyl; each R14 is independently H, C1-6alkyl, C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by halo, -OH, -O(C1-6alkyl), -N(Rx)(Ry), C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl, and the C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, or -N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with - O(C=O)C1-8alkyl); wherein (i) when Ring A is phenyl and R6 is selected from the group consisting of -NH2, -NHCH3, and -N(CH3)3, R1 and R2 are not both C1-2alkyl; (ii) when R1 and R2 are taken together with the N to which they are attached to form a 4- methylpiperazinyl, -(Ring A)-X-L-R6 is not
Figure imgf000044_0001
Attorney Docket No.: 185992002240 (iii) when R1 and R2 are taken together with the N to which they are attached to form a morpholinyl, R6 is not selected from the group consisting of -NH2, -NHC(O)CH3, and - NHC(O)O-C(CH3)3; and (iv) when Ring A is pyridin-4yl substituted with -NHC(CH3)phenyl, R1 and R2 are not taken together with the N to which they are attached to form an optionally substituted 2,5- diazabicyclo[2.2.2]octanyl. In some embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or salt of any of the foregoing, R1 and R2 are each independently C1-6alkyl, C2-6alkenyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R1 or R2 is optionally substituted with one or more R1a, the C3-8cycloalkyl of R1 or R2 is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, or C3-8cycloalkyl group of R1 or R2 are taken together with the atoms to which they are attached to form a C3- 8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1b; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R 13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R 14, - S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R3 is optionally substituted with one or more R3a, and optionally, two substituents of R3 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, Attorney Docket No.: 185992002240 wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl is optionally substituted one or more R3b; Ring A is 4- to 8-membered monocyclic cycloalkenyl, 4- to 8-membered unsaturated monocyclic heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 8-membered monocyclic cycloalkenyl, 4- to 8-membered unsaturated monocyclic heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 8-membered unsaturated monocyclic heterocyclyl or 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R14, - S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R4 is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4 is optionally substituted with one or more R4b, and the 3- to 8-membered heterocyclyl of R4 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-, wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)- is optionally substituted by one or more RL; each RL is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RL are taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R5 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-8cycloalkyl, wherein Attorney Docket No.: 185992002240 the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)2R14, -S(=O)N(R13)R14, -S(=O)OR14, or - S(=O)2N(R13)(R14), and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R13)(R14), -C(=NR15)N(R13)R14, - N(R13)S(=O)2R14, -S(=O)N(R13)R14, -S(=O)2N(R13)(R14), or 3- to 12-membered N-containing heterocyclyl, wherein the 3- to 12-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14, and the 3- to 12-membered N-containing heterocyclyl of R6 further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; R7, R8, R9, and R10 are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - OR11, -OR12, -SR12, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, - N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, - S(=O)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R7, R8, R9, or R10 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R7, R8, R9, or R10 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R7, R8, R9, or R10 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R7, R8, R9, or R10 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R7b; Attorney Docket No.: 185992002240 each R1a, R3a, R6a, or R7a is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, -CN, - N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, - OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, - C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, - S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R3a, R6a, or R7a is optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R3a, R6a, or R7a comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, -N(Rx)(Ry), oxo, - CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R11 is independently H, C1-6alkyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C1-6alkyl of R11 is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry) , and the phenyl or 5- to 6-membered heteroaryl of R11 is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R12 is independently H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, C1- 6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R13 is independently H, C1-6alkyl, or C3-8cycloalkyl; each R14 is independently H, C1-6alkyl, C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by halo, -OH, -O(C1-6alkyl), -N(Rx)(Ry), C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl, and Attorney Docket No.: 185992002240 the C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, or -N(R x)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with - O(C=O)C1-8alkyl); wherein (i) when Ring A is phenyl and R6 is selected from the group consisting of -NH2, -NHCH3, and -N(CH3)3, R1 and R2 are not both C1-2alkyl; (ii) when R1 and R2 are taken together with the N to which they are attached to form a 4- methylpiperazinyl, -(Ring A)-X-L-R6 is not
Figure imgf000049_0001
(iii) when R1 and R2 are taken together with the N to which they are attached to form a morpholinyl, R6 is not selected from the group consisting of -NH2, -NHC(O)CH3, and - NHC(O)O-C(CH3)3; and (iv) when Ring A is pyridin-4yl substituted with -NHC(CH3)phenyl, R1 and R2 are not taken together with the N to which they are attached to form an optionally substituted 2,5- diazabicyclo[2.2.2]octanyl. In some embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of formula (I), R1 and R2 are each independently C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), or C3-8cycloalkyl, wherein the C1-6alkyl of R1 or R2 is optionally substituted with one or more R1a, the C3-8cycloalkyl of R1 or R2 is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), or C3-8cycloalkyl group of R 1 or R2 are taken together with the atoms to which they are attached to form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein Attorney Docket No.: 185992002240 the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1b; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R3 is optionally substituted with one or more R3a, and optionally, two substituents of R3 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl is optionally substituted one or more R3b; Ring A is 4- to 8-membered monocyclic cycloalkenyl, 4- to 8-membered unsaturated monocyclic heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 8-membered monocyclic cycloalkenyl, 4- to 8-membered unsaturated monocyclic heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 8-membered unsaturated monocyclic heterocyclyl or 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein Attorney Docket No.: 185992002240 the C1-6alkyl of R4 is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4 is optionally substituted with one or more R4b, and the 3- to 8-membered heterocyclyl of R4 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-, wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)- is optionally substituted by one or more RL; each RL is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RL are taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R5 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R14, -S(=O)2R14, -S(=O)2N(R13)(R14), or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, or -S(=O)2N(R13)(R14), and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -OR12, -O-(3- to 12-membered N-containing heterocyclyl), -O-(5- to 6-membered N- containing heteroaryl), -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, - N(R13)C(=O)OR14, -OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R13)(R14), - C(=NR15)N(R13)R14, -N(R13)S(=O)2R14, -S(=O)N(R13)R14, -S(=O)2N(R13)(R14), or 3- to 12- membered N-containing heterocyclyl, wherein the 3- to 12-membered N-containing heterocyclyl, -O-(3- to 12-membered N- containing heterocyclyl), or -O-(5- to 6-membered N-containing heteroaryl) of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or - C(=O)OR14, and the 3- to 12-membered N-containing heterocyclyl of R6 optionally further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; Attorney Docket No.: 185992002240 R7, R8, R9, and R10 are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - OR11, -OR12, -SR12, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, - N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, - S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, - S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R7, R8, R9, or R10 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R7, R8, R9, or R10 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R7, R8, R9, or R10 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R7, R8, R9, or R10 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R7b; each R1a, R3a, R4a, R6a, or R7a is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, - CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, - OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, - C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, - S(=O)R14, -S(=O)2R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, - S(=NR15)OR14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R3a, R4a, R6a, or R7a is optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R3a, R4a, R6a, or R7a comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, -N(Rx)(Ry), oxo, - CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein Attorney Docket No.: 185992002240 the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; each R11 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R11 is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry), and the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R11 is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 12-membered heterocyclyl; each R12 is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R12 is optionally substituted with one or more halo, deuterium, C1-6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R13 is independently H, C1-6alkyl, or C3-8cycloalkyl; each R14 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, - N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl is optionally substituted by -OH, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, -OH, or -N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl) , wherein Attorney Docket No.: 185992002240 (i) when Ring A is phenyl and R6 is selected from the group consisting of -NH2, -NHCH3, and -N(CH3)3, R1 and R2 are not both C1-2alkyl; (ii) when R1 and R2 are taken together with the N to which they are attached to form a 4- methylpiperazinyl, -(Ring A)-X-L-R6 is not
Figure imgf000054_0001
(iii) when R1 and R2 are taken together with the N to which they are attached to form a morpholinyl, R6 is not selected from the group consisting of -NH2, -NHC(O)CH3, and - NHC(O)O-C(CH3)3; and (iv) when Ring A is pyridin-4yl substituted with -NHC(CH3)phenyl, R1 and R2 are not taken together with the N to which they are attached to form an optionally substituted 2,5- diazabicyclo[2.2.2]octanyl. In some embodiments of formula (I), R1 and R2 are each independently C1-6alkyl optionally substituted with one or more R1a; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, oxo, -OR 12, -N(Rx)(Ry), -CN, or -C(=O)N(R13)(R14), wherein the C1-6alkyl of R3 is optionally substituted with R3a; Ring A is 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 12-membered unsaturated heterocyclyl or 5- to 10-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, or -OR 12; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-, wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)- is optionally substituted by one or more RL; each RL is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, -CN, -N(R 13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - Attorney Docket No.: 185992002240 OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RL are taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R5 is H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), or - OR12, and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -OR12, -O-(3- to 12-membered N-containing heterocyclyl), -O-(5- to 6-membered N- containing heteroaryl), -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, - N(R13)C(=O)OR14, -OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), C(=O)N(R13)(R14), - N(R13)S(=O)2R14, -S(=O)N(R13)R14, -S(=O)2N(R13)(R14), -(C3-8cycloalkyl)N(Rx)(Ry), or 3- to 12-membered N-containing heterocyclyl, wherein the 3- to 12-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14, and the 3- to 12-membered N-containing heterocyclyl of R6 further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; R7 is H; R8 and R9 are each independently H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(O)R14, - N(R13)C(O)OR14, -N(R13)C(O)N(R13)R14, -OC(O)R14, -OC(O)OR14, -OC(O)N(R13)R14, - C(O)R14, -C(O)OR14, -C(O)N(R13)(R14), or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R8 or R9 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl of R8 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R8 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; R10 is H; each R1a, R3a, R6a, or R7a is independently -OR12 or -N(Rx)(Ry); each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, or -N(Rx)(Ry), wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R11 is independently H or C1-6alkyl; Attorney Docket No.: 185992002240 each R12 is independently H, C1-6alkyl, C2-6alkynyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R12 is optionally substituted with one or more halo, deuterium, or - N(Rx)(Ry); each R13 is independently H or C1-6alkyl; each R14 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by halo, -OH, -O(C1-6alkyl), -O(C=O)C1- 8alkyl), -N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, or - N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl); wherein (i) when Ring A is phenyl and R6 is selected from the group consisting of -NH2, -NHCH3, and -N(CH3)3, R1 and R2 are not both C1-2alkyl; (ii) when R1 and R2 are taken together with the N to which they are attached to form a 4- methylpiperazinyl, -(Ring A)-X-L-R6 is not
Figure imgf000056_0001
(iii) when R1 and R2 are taken together with the N to which they are attached to form a morpholinyl, R6 is not selected from the group consisting of -NH2, -NHC(O)CH3, and - NHC(O)O-C(CH3)3; and (iv) when Ring A is pyridin-4yl substituted with -NHC(CH3)phenyl, R1 and R2 are not taken together with the N to which they are attached to form an optionally substituted 2,5- diazabicyclo[2.2.2]octanyl. Attorney Docket No.: 185992002240 In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R1 and R2 are each independently C1-6alkyl optionally substituted with one or more R1a; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, oxo, -OR 12, or -N(Rx)(Ry) wherein the C1-6alkyl of R3 is optionally substituted with R3a; Ring A is 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 12-membered unsaturated heterocyclyl or 5- to 10-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, or -OR 12; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-, wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)- is optionally substituted by one or more RL; each RL is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, -CN, -N(R 13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RL are taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R5 is H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), or - OR12, and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), C(=O)N(R13)(R14), -N(R13)S(=O)2R14, - S(=O)N(R13)R14, -S(=O)2N(R13)(R14), or 3- to 12-membered N-containing heterocyclyl, wherein Attorney Docket No.: 185992002240 the 3- to 12-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14, and the 3- to 12-membered N-containing heterocyclyl of R6 further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; R7 is H; R8 and R9 are each independently H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(O)R14, - N(R13)C(O)OR14, -N(R13)C(O)N(R13)R14, -OC(O)R14, -OC(O)OR14, -OC(O)N(R13)R14, - C(O)R14, -C(O)OR14, or -C(O)N(R13)(R14) , wherein the C1-6alkyl of R8 or R9 is optionally substituted by one or more R7a; R10 is H; each R1a, R3a, R6a, or R7a is independently -OR12 or -N(Rx)(Ry); each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, or -N(Rx)(Ry), wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R11 is independently H or C1-6alkyl; each R12 is independently H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, or - N(Rx)(Ry); each R13 is independently H or C1-6alkyl; each R14 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by halo, -OH, -O(C1-6alkyl), -O(C=O)C1- 8alkyl), -N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, or - N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and Attorney Docket No.: 185992002240 the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl); wherein (i) when Ring A is phenyl and R6 is selected from the group consisting of -NH2, -NHCH3, and -N(CH3)3, R1 and R2 are not both C1-2alkyl; (ii) when R1 and R2 are taken together with the N to which they are attached to form a 4- methylpiperazinyl, -(Ring A)-X-L-R6 is not
Figure imgf000059_0001
(iii) when R1 and R2 are taken together with the N to which they are attached to form a morpholinyl, R6 is not selected from the group consisting of -NH2, -NHC(O)CH3, and - NHC(O)O-C(CH3)3; and (iv) when Ring A is pyridin-4yl substituted with -NHC(CH3)phenyl, R1 and R2 are not taken together with the N to which they are attached to form an optionally substituted 2,5- diazabicyclo[2.2.2]octanyl. In some embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of formula (I), R1 and R2 are taken together with the N to which they are attached to form a saturated 4- to 5- membered monocyclic heterocyclyl, saturated 7- to 10-membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl, wherein the saturated 4- to 5-membered monocyclic heterocyclyl, saturated 7- to 9-membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl is optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, oxo, -OR12, -N(Rx)(Ry), -CN, or -C(=O)N(R13)(R14), wherein the C1-6alkyl of R3 is optionally substituted with R3a; Ring A is 4- to 8-membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 8-membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4, and Attorney Docket No.: 185992002240 the 4- to 8-membered unsaturated heterocyclyl or 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, or -OR12; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-; R5 is H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), or - OR12, and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -OR12, -O-(3- to 12-membered N-containing heterocyclyl), -O-(5- to 6-membered N- containing heteroaryl), -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, - N(R13)C(=O)OR14, -OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R13)(R14), - N(R13)S(=O)2R14, -S(=O)N(R13)R14, -S(=O)2N(R13)(R14), -(C3-8cycloalkyl)N(Rx)(Ry), or 3- to 8-membered N-containing heterocyclyl, wherein the -O-(3- to 8-membered N-containing heterocyclyl), -O-(5- to 6-membered N- containing heteroaryl), or 3- to 8-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or - C(=O)OR14, and the 3- to 8-membered N-containing heterocyclyl of R6 optionally further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; R7 is H or halo; R8 and R9 are each independently H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(O)R14, - N(R13)C(O)OR14, -N(R13)C(O)N(R13)R14, -OC(O)R14, -OC(O)OR14, -OC(O)N(R13)R14, - C(O)R14, -C(O)OR14, -C(O)N(R13)(R14), C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R8 or R9 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl of R8 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R8 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; R10 is H; each R1a, R3a, R4a, R6a, or R7a is independently -OR12 or -N(Rx)(Ry); each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, or -N(Rx)(Ry), wherein Attorney Docket No.: 185992002240 the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R11 is independently H or C1-6alkyl; each R12 is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, or 5- to 10- membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, - O(C1-6alkyl), or -N(Rx)(Ry); each R13 is independently H, C1-6alkyl, or C3-8cycloalkyl; each R14 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, - N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl of R14 is optionally substituted by -OH, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, -OH, or -N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl), wherein when Ring A is phenyl, then -L-R6 is not -NH2 or -OCH3. In some embodiments of the foregoing, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of formula (I), R1 and R2 are taken together with the N to which they are attached to form a saturated 4- to 5- membered monocyclic heterocyclyl, saturated 7- to 10-membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl, wherein Attorney Docket No.: 185992002240 the saturated 4- to 5-membered monocyclic heterocyclyl, saturated 7- to 9-membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl is optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, oxo, -OR12, -N(Rx)(Ry), -CN, or -C(=O)N(R13)(R14), wherein the C1-6alkyl of R3 is optionally substituted with R3a; Ring A is 4- to 8-membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 8-membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 8-membered unsaturated heterocyclyl or 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, or -OR12; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-; R5 is H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), or - OR12, and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -OR12, -O-(3- to 12-membered N-containing heterocyclyl), -O-(5- to 6-membered N- containing heteroaryl), -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, - N(R13)C(=O)OR14, -OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R13)(R14), - N(R13)S(=O)2R14, -S(=O)N(R13)R14, -S(=O)2N(R13)(R14), -(C3-8cycloalkyl)N(Rx)(Ry), or 3- to 8-membered N-containing heterocyclyl, wherein the -O-(3- to 8-membered N-containing heterocyclyl), -O-(5- to 6-membered N- containing heteroaryl), or 3- to 8-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or - C(=O)OR14, and the 3- to 8-membered N-containing heterocyclyl of R6 optionally further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; R7 is H or halo; R8 and R9 are each independently H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(O)R14, - N(R13)C(O)OR14, -N(R13)C(O)N(R13)R14, -OC(O)R14, -OC(O)OR14, -OC(O)N(R13)R14, - Attorney Docket No.: 185992002240 C(O)R14, -C(O)OR14, -C(O)N(R13)(R14), C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R8 or R9 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl of R8 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R8 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; R10 is H; each R1a, R3a, R4a, R6a, or R7a is independently -OR12 or -N(Rx)(Ry); each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, or -N(Rx)(Ry), wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R11 is independently H or C1-6alkyl; each R12 is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, or 5- to 10- membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, - O(C1-6alkyl), or -N(Rx)(Ry); each R13 is independently H or C1-6alkyl, each R14 is independently H, C1-6alkyl, C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -N(Rx)(Ry), C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12- membered heterocyclyl, and the C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, or -N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl), wherein Attorney Docket No.: 185992002240 when Ring A is phenyl, then -L-R6 is not -NH2 or -OCH3. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing: R1 and R2 are each independently C1-6alkyl optionally substituted with one or more R1a; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, oxo, -OR 12, or -N(Rx)(Ry) wherein the C1-6alkyl of R3 is optionally substituted with R3a; Ring A is 4- to 8-membered monocyclic cycloalkenyl, 4- to 8-membered unsaturated monocyclic heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 8-membered monocyclic cycloalkenyl, 4- to 8-membered unsaturated monocyclic heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 8-membered unsaturated monocyclic heterocyclyl or 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, or -OR 12; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-; R5 is H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), or - OR12, and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is (i) -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)N(R13)R14, -C(=O)N(R13)(R14), -N(R13)S(=O)2R14, -S(=O)N(R13)R14, - S(=O)2N(R13)(R14), or 3- to 12-membered N-containing heterocyclyl, wherein the 3- to 12-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or - C(=O)OR14, and the 3- to 12-membered N-containing heterocyclyl of R6 further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; or (ii) -OC(=O)(C1-6alkyl)N(Rx)(Ry), -OC(=O)O(C1-6alkyl)N(Rx)(Ry), -C(=O)(C1- 6alkyl)N(Rx)(Ry), -C(=O)O(C1-6alkyl)N(Rx)(Ry), -S(=O)(C1-6alkyl)N(Rx)(Ry), - Attorney Docket No.: 185992002240 S(=O)(C1-6alkyl)N(Rx)(Ry), -S(=O)O(C1-6alkyl)N(Rx)(Ry), or -S(=O)2(C1- 6alkyl)N(Rx)(Ry), wherein the -OC(=O)(C1-6alkyl)N(Rx)(Ry), -OC(=O)O(C1-6alkyl)N(Rx)(Ry), -C(=O)(C1- 6alkyl)N(Rx)(Ry), -C(=O)O(C1-6alkyl)N(Rx)(Ry), -S(=O)(C1-6alkyl)N(Rx)(Ry), -S(=O)(C1-6alkyl)N(Rx)(Ry), -S(=O)O(C1-6alkyl)N(Rx)(Ry), or -S(=O)2(C1- 6alkyl)N(Rx)(Ry) of R6 is optionally substituted with one or more halo, -OH, - O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, -N(Rx)(Ry), C3-8cycloalkyl, phenyl, phenol, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl; R7 is H; R8 and R9 are each independently H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(O)R14, - N(R13)C(O)OR14, -N(R13)C(O)N(R13)R14, -OC(O)R14, -OC(O)OR14, -OC(O)N(R13)R14, - C(O)R14, -C(O)OR14, or -C(O)N(R13)(R14) , wherein the C1-6alkyl of R8 or R9 is optionally substituted by one or more R7a; R10 is H; each R1a, R3a, R6a, or R7a is independently -OR12 or -N(Rx)(Ry); each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, or -N(Rx)(Ry), wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R11 is independently H or C1-6alkyl; each R12 is independently H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, or - N(Rx)(Ry); each R13 is independently H or C1-6alkyl; each R14 is independently H, C1-6alkyl, C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by halo, -OH, -O(C1-6alkyl), -N(Rx)(Ry), C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl, and the C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, or -N(Rx)(Ry) each R15 is independently H or C1-6alkyl; and Attorney Docket No.: 185992002240 each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl); wherein (i) when Ring A is phenyl and R6 is selected from the group consisting of -NH2, -NHCH3, and -N(CH3)3, R1 and R2 are not both C1-2alkyl; (ii) when R1 and R2 are taken together with the N to which they are attached to form a 4- methylpiperazinyl, -(Ring A)-X-L-R6 is not
Figure imgf000066_0001
(iii) when R1 and R2 are taken together with the N to which they are attached to form a morpholinyl, R6 is not selected from the group consisting of -NH2, -NHC(O)CH3, and - NHC(O)O-C(CH3)3; and (iv) when Ring A is pyridin-4yl substituted with -NHC(CH3)phenyl, R1 and R2 are not taken together with the N to which they are attached to form an optionally substituted 2,5- diazabicyclo[2.2.2]octanyl. In some embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R1 and R2 are each independently C1-6alkyl optionally substituted with one or more R1a; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, oxo, -OR 12, or -N(Rx)(Ry) wherein the C1-6alkyl of R3 is optionally substituted with R3a; Ring A is 4- to 8-membered monocyclic cycloalkenyl, 4- to 8-membered unsaturated monocyclic heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein Attorney Docket No.: 185992002240 the 4- to 8-membered monocyclic cycloalkenyl, 4- to 8-membered unsaturated monocyclic heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 8-membered unsaturated monocyclic heterocyclyl or 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, or -OR12; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-; R5 is H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), or - OR12, and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R13)(R14), -N(R13)S(=O)2R14, - S(=O)N(R13)R14, -S(=O)2N(R13)(R14), or 3- to 12-membered N-containing heterocyclyl, wherein the 3- to 12-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14, and the 3- to 12-membered N-containing heterocyclyl of R6 further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; R7 is H; R8 and R9 are each independently H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(O)R14, - N(R13)C(O)OR14, -N(R13)C(O)N(R13)R14, -OC(O)R14, -OC(O)OR14, -OC(O)N(R13)R14, - C(O)R14, -C(O)OR14, or -C(O)N(R13)(R14) , wherein the C1-6alkyl of R8 or R9 is optionally substituted by one or more R7a; R10 is H; each R1a, R3a, R6a, or R7a is independently -OR12 or -N(Rx)(Ry); each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, or -N(Rx)(Ry), wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R11 is independently H or C1-6alkyl; each R12 is independently H, C1-6alkyl, or C3-8cycloalkyl, Attorney Docket No.: 185992002240 wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, or - N(Rx)(Ry); each R13 is independently H or C1-6alkyl; each R14 is independently H, C1-6alkyl, C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by halo, -OH, -O(C1-6alkyl), -N(Rx)(Ry), C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl, and the C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, or -N(Rx)(Ry) each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl); wherein (i) when Ring A is phenyl and R6 is selected from the group consisting of -NH2, -NHCH3, and -N(CH3)3, R1 and R2 are not both C1-2alkyl; (ii) when R1 and R2 are taken together with the N to which they are attached to form a 4- methylpiperazinyl, -(Ring A)-X-L-R6 is not
Figure imgf000068_0001
(iii) when R1 and R2 are taken together with the N to which they are attached to form a morpholinyl, R6 is not selected from the group consisting of -NH2, -NHC(O)CH3, and - NHC(O)O-C(CH3)3; and (iv) when Ring A is pyridin-4yl substituted with -NHC(CH3)phenyl, R1 and R2 are not taken together with the N to which they are attached to form an optionally substituted 2,5- diazabicyclo[2.2.2]octanyl. In some embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Attorney Docket No.: 185992002240 In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; R8 is H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(O)R14, -N(R13)C(O)OR14, - N(R13)C(O)N(R13)R14, -C(O)N(R13)(R14), or C3-6cycloalkyl, wherein the C1-6alkyl of R8 is optionally substituted by one or more R7a; and R9 is H, halo, C1-6alkyl, -OR12, -CN, or C3-6cycloalkyl, wherein the C1-6alkyl of R9 is optionally substituted by one or more R7a. In some embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R1 and R2 are taken together with the N to which they are attached to form a 4- to 12- membered heterocyclyl optionally substituted with one or more R3; Ring A is pyridinyl; and L is a bond or -O-(C1-6alkyl)-. In some embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R1 and R2 are taken together with the N to which they are attached to form a 4- to 12- membered heterocyclyl optionally substituted with one or more R3; Ring A is pyridinyl; L is a bond; and R6 is piperazinyl optionally substituted with one or more R6b. In some embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, Attorney Docket No.: 185992002240 R1 and R2 are taken together with the N to which they are attached to form a 4- to 12- membered heterocyclyl optionally substituted with one or more R3; and R8 and R9 are each independently H, F, -N(CH3)(CH3), -OCH3 or -OCD3. In some embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, (i) when Ring A is phenyl and R6 is selected from the group consisting of -NH2, - NHCH3, and -N(CH3)3, R1 and R2 are not both C1-2alkyl; (ii) when R1 and R2 are taken together with the N to which they are attached to form a 4-methylpiperazinyl, -(Ring A)-X-L-R6 is not
Figure imgf000070_0001
(iii) when R1 and R2 are taken together with the N to which they are attached to form a morpholinyl, R6 is not selected from the group consisting of -NH2, -NHC(O)CH3, and -NHC(O)O-C(CH3)3; and (iv) when Ring A is pyridin-4yl substituted with -NHC(CH3)phenyl, R1 and R2 are not taken together with the N to which they are attached to form an optionally substituted 2,5-diazabicyclo[2.2.2]octanyl. In some embodiments, when Ring A is phenyl, then -L-R6 is not -NH2 or -OCH3. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, Ring A is phenyl or 5- to 6-membered heteroaryl. In some embodiments, Ring A is selected from the group consisting of phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furan, thiophene, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, and triazinyl. In some embodiments, Ring A is phenyl, thiazolyl, or pyridinyl. In some embodiments, Ring A is 4- to 8-membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 8- membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6- membered heteroaryl of Ring A is optionally substituted by one or more R4; and the 4- to 8- membered unsaturated heterocyclyl or 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S. In some embodiments, Ring Attorney Docket No.: 185992002240 A is phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4; and the 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S. In some embodiments, Ring A is phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R1 and R2 are each independently C1-6alkyl optionally substituted with one or more R1a. In some embodiments, R1 and R2 are each independently C1-4alkyl optionally substituted with one or more R1a. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, each R1a is independently -OH, -NH2, -NH(C1-6alkyl), -N(C1- 6alkyl)(C1-6alkyl), -NH(C3-6cycloalkyl), or -N(C1-6alkyl)(C3-6cycloalkyl). In some embodiments, each R1a is independently -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -NH(C3-6cycloalkyl), or -N(C1-4alkyl)(C3-6cycloalkyl). In some embodiments, each R 1a is independently -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -NH(C3-6cycloalkyl), or - N(C1-4alkyl)(C3-6cycloalkyl). In some embodiments, each R 1a is independently -OH, -NH2, - NH(CH3), -N(CH3)(CH3), -NH(CH2CH3), -N(CH3)(CH2CH3), or -N(CH2CH3)(CH2CH3). In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R1 and R2 are taken together with the N to which they are attached to form a 3- to 12-membered heterocyclyl optionally substituted with one or more R3, wherein the 3- to 12-membered heterocyclyl comprises a 3- to 8-membered monocyclic heterocyclyl, a 5- to 12-membered fused heterocyclyl, or a 6- to 12-membered spirocyclic heterocyclyl. In some embodiments, R1 and R2 are taken together with the N to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with one or more R3. In some embodiments, R1 and R2 are taken together with the N to which they are attached to form a 4- to 7-membered monocyclic heterocyclyl optionally substituted with one or more R3. In some embodiments, R1 and R2 are taken together with the N to which they are attached to form an azetidinyl, pyrrolidinyl, or diazepanyl optionally substituted with one or more R3. In some embodiments, R1 and R2 are taken together with the N to which they are attached to form a pyrrolidinyl or diazepanyl optionally substituted with one or more R3. In some embodiments, R1 and R2 are taken together with the N to which they are attached to Attorney Docket No.: 185992002240 form a 6- to 12-membered fused heterocyclyl optionally substituted with one or more R3. In some embodiments, R1 and R2 are taken together with the N to which they are attached to form a 6- to 12-membered spirocyclic heterocyclyl optionally substituted with one or more R3. In some embodiments, R1 and R2 are taken together with the N to which they are attached to form a saturated 4- to 5-membered monocyclic heterocyclyl, saturated 7- to 9- membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl, wherein the saturated 4- to 5-membered monocyclic heterocyclyl, saturated 7- to 9-membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl is optionally substituted with one or more R3. In some embodiments, R1 and R2 are taken together with the N to which they are attached to form a saturated 4- to 5-membered monocyclic heterocyclyl optionally substituted with one or more R3. In some embodiments, R1 and R2 are taken together with the N to which they are attached to form a saturated 7- to 10-membered fused heterocyclyl optionally substituted with one or more R3. In some embodiments, R1 and R2 are taken together with the N to which they are attached to form a saturated 7- to 9-membered fused heterocyclyl optionally substituted with one or more R3. In some embodiments, R1 and R2 are taken together with the N to which they are attached to form a saturated 7- to 10- membered spirocyclic heterocyclyl optionally substituted with one or more R3. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, each R3 is independently halo, C2-6alkyl, C2-6alkenyl, C2- 6alkynyl, oxo, -OR12, -SR12, -N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, - N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -SC(=O)R14, -SC(=O)N(R13)R14, -SC(=O)OR14, -C(=O)R14, - C(=O)N(R13)(R14), -C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, - C(=NR15)OR14, -N(R13)S(=O)2R14, -S(=O)R14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3- 8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C2-6alkyl of R 3 is optionally substituted with one or more R3a, and optionally, two substituents of R3 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted one or more R3b. Attorney Docket No.: 185992002240 In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, each R3 is independently halo, C2-6alkyl, oxo, -OR 12, or - N(Rx)(Ry) wherein the C2-6alkyl of R3 is optionally substituted with R3a. In some embodiments, each R3 is independently halo, -OH, C1-6alkyl, C1-6alkoxy, oxo, or -N(Rx)(Ry) wherein the C1-6alkyl of the R3 is optionally substituted with R3a. In some embodiments, each R3 is independently halo, -OH, C1-4alkyl, C1-4alkoxy, oxo, -NH2, -NH(C1-4alkyl), -N(C1- 4alkyl)(C1-4alkyl), -NH(C3-6cycloalkyl), or -N(C1-4alkyl)(C3-6cycloalkyl), wherein the C1- 4alkyl of the R3 is optionally substituted with R3a. In some embodiments, each R3 is independently F, -OH, -CH 3 3, -CH2OH, -OCH3, oxo, or -NH2. In some embodiments, each R is independently -OH, C1-6alkyl, C1-6alkoxy, or -N(Rx)(Ry) wherein the C1-6alkyl of the R 3 is optionally substituted with R3a. In some embodiments, each R3 is independently -OH, C1- 4alkyl, C1-4alkoxy, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -NH(C3-6cycloalkyl), or - N(C1-4alkyl)(C3-6cycloalkyl), wherein the C1-4alkyl of the R3 is optionally substituted with R3a. In some embodiments, each R3 is independently -OH, -CH3, -CH2OH, -OCH3, or -NH2. In some embodiments, R3 is independently C1-6alkyl or oxo. In some embodiments, each R3 is independently -CH3 or oxo. In some embodiments, each R 3 is halo. In some embodiments, R3 is F. In some embodiments, each R3 is independently halo, C1-6alkyl, oxo, -OR 12, - N(Rx)(Ry), -CN, or -C(=O)N(R13)(R14), wherein the C1-6alkyl of R 3 is optionally substituted with R3a. In some embodiments, each R3 is independently halo, C2-6alkyl, oxo, -OR 12, - N(Rx)(Ry), -CN, or -C(=O)N(R13)(R14), wherein the C1-6alkyl of R 3 is optionally substituted with R3a. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group consisting of
Figure imgf000073_0001
Figure imgf000073_0002
Attorney Docket No.: 185992002240
Figure imgf000074_0001
In some embodiments, R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group consisting
Figure imgf000074_0002
Figure imgf000074_0003
Attorney Docket No.: 185992002240
Figure imgf000075_0001
In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group consisting of
Figure imgf000075_0002
some embodi 1
Figure imgf000075_0003
ments, R and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group consisting
Figure imgf000075_0004
Figure imgf000075_0005
some embodiments, R1 and R2 are taken together with the N to which they are Attorney Docket No.: 185992002240 attached to form a heterocyclyl selected from the group consisting
Figure imgf000076_0001
Figure imgf000076_0002
,
Figure imgf000076_0003
some embodiments, R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group consisting of
Figure imgf000076_0004
In some embodiments, R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group consisting
Figure imgf000076_0005
Figure imgf000076_0006
Attorney Docket No.: 185992002240 In some embodiments, R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group consisting
Figure imgf000077_0001
Figure imgf000077_0002
some embodiments, R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group consisting
Figure imgf000077_0003
Figure imgf000077_0004
some embodiments, R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group consisting
Figure imgf000077_0005
Attorney Docket No.: 185992002240
Figure imgf000078_0001
In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, each R4 is independently halo or -O-(C1-6alkyl). In some embodiments, each R4 is independently halo or -OCH3. In some embodiments, each R 4 is independently F, Cl, or -OCH3. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R5 is H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), -OR12; and the C3-8cycloalkyl of R5 is optionally substituted with one or more R5b. In some embodiments, R5 is H, C1-6alkyl, or C3-8cycloalkyl. In some embodiments, R5 is H or C1-6alkyl. In some embodiments, R 5 is H. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, L is a bond or -O-(C1-6alkyl)-. In some embodiments, L is a bond or -O-(CH2CH2)-. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R6 is -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)OR14, - N(R13)C(=O)N(R13)R14, -C(=O)N(R13)(R14), -C(=O)(C1-6alkyl)N(Rx)(Ry), or 3- to 12- membered N-containing heterocyclyl optionally substituted with one or more R6b. In some embodiments, R6 is -N(Rx)(Ry), -N(R13)C(=O)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), or 3- to 12- membered N-containing heterocyclyl optionally substituted with one or more R6b. In some embodiments, R6 is -N(Rx)(Ry), -N(R13)C(=O)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), azetidinyl, or piperazinyl, wherein the azetidinyl or piperazinyl of R6 is optionally substituted with one or Attorney Docket No.: 185992002240 more R6b. In some embodiments, R6 is -N(Rx)(Ry). In some embodiments, R6 is - N(R13)C(=O)R14, -N(R13)C(=O)OR14, -N(R13)C(=O)N(R13)R14, -C(=O)N(R13)(R14), or - C(=O)(C1-6alkyl)N(Rx)(Ry). In some embodiments, R6 is -N(R13)C(=O)R14 or -C(=O)(C1- 6alkyl)N(Rx)(Ry). In some embodiments, R6 is 3- to 12-membered N-containing heterocyclyl optionally substituted with one or more R6b. In some embodiments, R6 is azetidinyl, pyrrolidinyl, or piperazinyl, wherein the azetidinyl, pyrrolidinyl, or piperazinyl is optionally substituted with one or more R6b. In some embodiments, R6 is azetidinyl or piperazinyl, wherein the azetidinyl or piperazinyl is optionally substituted with one or more R6b. In some embodiments, R6 is -OR12, -N(Rx)(Ry), -N(R13)C(=O)R14, - N(R13)C(=O)OR14, -N(R13)C(=O)N(R13)R14, -C(=O)N(R13)(R14), -C(=O)(C1- 6alkyl)N(Rx)(Ry), or 3- to 12-membered N-containing heterocyclyl optionally substituted with one or more R6b. In some embodiments, R6 is -OR12, -N(Rx)(Ry), -N(R13)C(=O)R14, - N(R13)C(=O)OR14, -N(R13)C(=O)N(R13)R14, -C(=O)N(R13)(R14), -C(=O)(C1- 6alkyl)N(Rx)(Ry), or 3- to 8-membered N-containing heterocyclyl optionally substituted with one or more R6b. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, L is a bond and R6 is 3- to 12-membered N-containing heterocyclyl optionally substituted with one or more R6b. In some embodiments, L is a bond and R6 is azetidinyl or piperazinyl, wherein the azetidinyl or piperazinyl is optionally substituted with one or more R6b. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R6 is selected from the group consisting of
Figure imgf000079_0001
,
Figure imgf000079_0002
Attorney Docket No.: 185992002240
Figure imgf000080_0001
some embodiments, R6 is selected from the group consisting of
Figure imgf000080_0002
. In some
Figure imgf000080_0003
In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R8 and R9 are each independently H, halo, -N(Rx)(Ry), -OR11, -N(R13)C(O)R14, or -N(R13)C(O)OR14. In some embodiments, R8 and R9 are each independently H, halo, -NH2, -N(C1-6alkyl)(C1-6alkyl), -O(C1-6alkyl), -NHC(O)(5- to 6- membered aryl), or -NHC(O)O(C1-6alkyl), wherein the 5- to 6-membered aryl of -NHC(O)(5- to 6-membered aryl) is optionally substituted with -N(C1-6alkyl)(C1-6alkyl). In some embodiments, R8 and R9 are each independently H, F, Cl, -NH2, -N(CH3)(CH3), -OCH3, - NHC(O)(phenyl), or -NHC(O)O(CH2CH3), wherein the phenyl of -NHC(O)(phenyl) is substituted with -N(CH3)(CH3). In some embodiments, R 8 and R9 are each H. In some embodiments, each R12 is independently H, C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-8cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, -O(C1-6alkyl), or -N(Rx)(Ry). In some embodiments, each R12 is independently H, C1-6alkyl, C3-8cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, Attorney Docket No.: 185992002240 or -N(Rx)(Ry). In some embodiments, each R12 is independently H, C1-6alkyl, or C3- 8cycloalkyl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, or -N(Rx)(Ry). In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R14 is selected from the group consisting
Figure imgf000081_0001
Figure imgf000081_0002
aforementioned R14 groups have the (R)- configuration. In some embodiments, the aforementioned R14 groups have the (S)- configuration.
Attorney Docket No.: 185992002240 In some embodiments of a compound of formula (I), the compound is a compound of formula (II):
Figure imgf000082_0001
any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein X1 is N or CH, and n is 0, 1, 2, or 3, and R1, R2, R4, R6, R7, R8, R9, R10 and L are as defined elsewhere herein. In another variation, X1 is N or CH, and n is 0, 1, 2, or 3, and R1, R2, R4, R6, R7, R8, R9, R10 and L are as defined for a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments of formula (II), X1 is N. In some embodiments, X1 is CH. In some embodiments of formula (II), n is 0, 1, or 2. In some embodiments In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments of a compound of formula (I), the compound is a compound of formula (II-A):
Figure imgf000082_0002
any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein X1 is N or CH, and R1, R2, R6, R8, R9, and L are as defined elsewhere herein. In another variation, X1 is N or CH, and R1, R2, R6, R8, R9, and L are as defined for a compound of formula (I), or a stereoisomer or tautomer thereof, or a Attorney Docket No.: 185992002240 pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some of the foregoing embodiments, provided herein is a compound of formula (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments of a compound of formula (I), the compound is a compound of formula (II-B):
Figure imgf000083_0001
any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R1, R2, R4, R6, R7, R8, R9, R10 and L are as defined elsewhere herein. In another variation, R1, R2, R4, R6, R7, R8, R9, R10 and L are as defined for a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (II-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is a compound of formula (II-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments of a compound of formula (I), the compound is a compound of formula (II-C):
Figure imgf000083_0002
any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R1, R2, R4, R6, R7, R8, R9, R10 and L are as defined elsewhere herein. In another variation, R1, R2, R4, R6, R7, R8, R9, R10 and L are as defined for a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically Attorney Docket No.: 185992002240 acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is a compound of formula (II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments of a compound of formula (I), the compound is a compound of formula (II-D)
Figure imgf000084_0001
any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein X1 is N or CH; n is 0, 1, 2, or 3; R3c is H or C1-4alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and R4, R6, R7, R8, R9, R10 and L are as defined elsewhere herein. In another variation, X1 is N or CH; n is 0, 1, 2, or 3; R3c is H or C1-4alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and R4, R6, R7, R8, R9, R10 and L are as defined for a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (II-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is a compound of formula (II-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments of formula (II-D), X1 is N. In some embodiments, X1 is CH. In some embodiments of formula (II-D), n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments of formula (II-D), R3c is H or methyl. In some embodiments, R3c is H. In some embodiments, R3c is C1-4alkyl. In some embodiments, R 3c is methyl. Attorney Docket No.: 185992002240 In some embodiments of formula (II-D), p is 0, 1, 2, 3, or 4. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments of a compound of formula (I), the compound is a compound of formula (II-D-1)
Figure imgf000085_0001
any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein X1 is N or CH; R3c is H or C1-4alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and R3, R7, R8, R9, R10, and L are as defined elsewhere herein. In another variation, X1 is N or CH; p is 0, 1, 2, 3, 4, 5, or 6; and R3, R7, R8, R9, R10, and L are as defined for a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (II-D-1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is a compound of formula (II-D-1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments of formula (II-D-1), R3c is H or methyl. In some embodiments, R3c is H. In some embodiments, R3c is C1-4alkyl. In some embodiments, R 3c is methyl. In some embodiments of formula (II-D-1), p is 0, 1, 2, 3, or 4. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. Attorney Docket No.: 185992002240 In some embodiments of a compound of formula (I), the compound is a compound of formula (II-D-2)
Figure imgf000086_0001
any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein X1 is N or CH; R3c is H or C1-4alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and R3, R8, R9, and L are as defined elsewhere herein. In another variation, X1 is N or CH; p is 0, 1, 2, 3, 4, 5, or 6; and R3, R8, R9, and L are as defined for a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (II-D-2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is a compound of formula (II-D-2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments of formula (II-D-2), R3c is H or methyl. In some embodiments, R3c is H. In some embodiments, R3c is C1-4alkyl. In some embodiments, R 3c is methyl. In some embodiments of formula (II-D-2), p is 0, 1, 2, 3, or 4. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. Attorney Docket No.: 185992002240 In some embodiments of a compound of formula (I), the compound is a compound of formula (III):
Figure imgf000087_0001
any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein X1 is N or CH; n is 0, 1, 2, or 3; and R1, R2, R4, R6, R7, R8, R9, R10 and L are as defined elsewhere herein. In another variation, X1 is N or CH; n is 0, 1, 2, or 3; and R1, R2, R4, R6, R7, R8, R9, R10 and L are as defined for a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is a compound of formula (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments of a compound of formula (I), the compound is a compound of formula (III-A):
Figure imgf000087_0002
any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein X1 is N or CH; and R1, R2, R6, R8, R9, and L are as defined elsewhere herein. In another variation, X1 is N or CH; and R1, R2, R6, R8, R9, and L are as defined for a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (III-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the Attorney Docket No.: 185992002240 foregoing, the compound is a compound of formula (III-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments of a compound of formula (I), the compound is a compound of formula (III-B):
Figure imgf000088_0001
any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R1, R2, R4, R6, R7, R8, R9, R10 and L are as defined elsewhere herein. In another variation, R1, R2, R4, R6, R7, R8, R9, R10 and L are as defined for a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (III-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is a compound of formula (III-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments of a compound of formula (I), the compound is a compound of formula (IV):
Figure imgf000088_0002
any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein X2, X4 and X5 are each independently C, N, O or S; X3 and X6 are each independently C or N; n is 0, 1, 2, or 3, and R1, R2, R4, R6, R7, R8, R9, R10 and L are as defined elsewhere herein. In another variation, X2, X4 and X5 are each independently C, N, O or S; X3 and X6 are each independently C or N; n is 0, 1, 2, or 3, and R1, R2, R4, R6, R7, R8, Attorney Docket No.: 185992002240 R9, R10 and L are as defined for a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (IV), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is a compound of formula (IV), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments of a compound of formula (I), the compound is a compound of formula (IV-A):
Figure imgf000089_0001
any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R1, R2, R6, R7, R8, R9, R10 and L are as defined elsewhere herein. In another variation, R1, R2, R6, R7, R8, R9, R10 and L are as defined for a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is a compound of formula (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments, the compounds of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, selectively modulate TDP-43. In some embodiments, the compounds of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, reduce TDP-43 cytoplasmic inclusions, improve nuclear TDP-43 function, or reduce neurodegeneration. In some embodiments, the compounds of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, reduce TDP-43 cytoplasmic inclusions. In some embodiments, the compounds of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or Attorney Docket No.: 185992002240 a pharmaceutically acceptable salt of any of the foregoing, improve nuclear TDP-43 function. In some embodiments, the compounds of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, reduce neurodegeneration. In some embodiments, the compounds of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, mitigate TDP-43 cytoplasmic condensates in motor neurons. In some embodiments, the motor neurons are iPSC-derived motor neurons. In some embodiments, STMN2 and POLDIP3 splicing in iPSC-derived motor neurons is restored. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is selected from Table 1. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is selected from examples 1-68 of Table 1. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is selected from Table 1, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is selected from compounds 1-68 of Table 1, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is selected from compounds 1- 43, or 45-68 of Table 1, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is selected from compounds 1-43, 45-361, 363-367, 370-399, and 404-405 of Table 1, or a pharmaceutically acceptable salt of any of the foregoing. Attorney Docket No.: 185992002240 Table 1
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In some embodiments, provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein the compound is selected from the group consisting of Attorney Docket No.: 185992002240 1-(4-(5-(6,7-dimethoxy-4-(pyrrolidin-1-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one; (1-(2-(6-(azetidin-1-yl) pyridin-3-yl)-6-fluoro-7-methoxyquinolin-4-yl) pyrrolidin-3- yl) methanol; 2-(4-(5-(6-fluoro-4-(3-(hydroxymethyl) pyrrolidin-1-yl)-7-methoxyquinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-ol; (1-(2-(2-(azetidin-1-yl) thiazol-5-yl)-6-fluoro-7-methoxyquinolin-4-yl) pyrrolidin-3- yl) methanol; (1-(2-(6-(azetidin-1-yl) pyridin-3-yl)-7-(dimethylamino)-6-fluoroquinolin-4-yl) pyrrolidin-3-yl) methanol; 2-(2-(6-(dimethylamino) pyridin-3-yl)-7-methoxyquinolin-4-yl) octahydro-6H- pyrrolo[3,4-c] pyridin-6-one; 6,7-dimethoxy-2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(pyrrolidin-1-yl) quinoline; 2-(4-(5-(6,7-dimethoxy-4-(pyrrolidin-1-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-ol; 1-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-3-methylpyrrolidin-3- ol; (1-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) pyrrolidin-3-yl) methanol; 2-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-2,7-diazaspiro [4.5] decane; 4-(2-methylpyrrolidin-1-yl)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline; 2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(pyrrolidin-1-yl) quinoline; 2-(2-(6-(azetidin-3-yl) pyridin-3-yl)-7-methoxyquinolin-4-yl)-2,7-diazaspiro [4.5] decane; 6-methoxy-4-(3-methoxypyrrolidin-1-yl)-N, N-dimethyl-2-(4-(2-(methylamino) ethoxy) phenyl) quinolin-7-amine; 4-(3-methoxypyrrolidin-1-yl)-N, N-dimethyl-2-(6-(2-(methylamino) ethoxy) pyridin- 3-yl) quinolin-7-amine; 2-(6-fluoro-7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-2,7- diazaspiro [4.5] decane; (1-(6-fluoro-7-methoxy-2-(6-(methylamino) pyridin-3-yl) quinolin-4-yl) pyrrolidin-3- yl) methanol; Attorney Docket No.: 185992002240 5-(6-fluoro-7-methoxy-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-2-yl)-N- methylpyridin-2-amine; 2-(6-(piperazin-1-yl)pyridin-3-yl)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinoline; (1-(2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) pyrrolidin-3-yl) methanol; 2-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-7-methyl-2,7- diazaspiro [4.5] decane; 7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(2,6-diazaspiro [3.4] octan-6-yl) quinoline; 2-(7-methoxy-2-(4-(piperazin-1-yl) phenyl) quinolin-4-yl)-2,7-diazaspiro [4.5] decane; 2-(4-(7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2-yl) phenoxy)-N-methylethan-1-amine; 6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl)-2-(6-(piperazin-1- yl) pyridin-3-yl) quinoline; 6-fluoro-N, N-dimethyl-2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-7-amine; 2-(4-(6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2-yl) phenoxy)-N-methylethan-1-amine; 5-(7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2-yl)-N, N- dimethylpyridin-2-amine; (1-(2-(6-(2-(cyclopropylamino) ethoxy) pyridin-3-yl)-6-fluoro-7-methoxyquinolin-4- yl) pyrrolidin-3-yl) methanol; 2-amino-1-(5-(6-fluoro-4-(3-(hydroxymethyl) pyrrolidin-1-yl)-7-methoxyquinolin-2- yl) pyridin-2-yl) propan-1-one; 2-(2-(6-(azetidin-1-yl) pyridin-3-yl)-6-fluoro-7-methoxyquinolin-4-yl)-2,7-diazaspiro [4.5] decane; 2-amino-1-(4-(5-(7-methoxy-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl) propan-1-one; 4-hexahydropyrrolo[3,4-c] pyrrol-2(1H)-yl)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline; 1-(4-(5-(4-(3,6-diazabicyclo [3.2.0] heptan-3-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl)-2-aminopropan-1-one; 2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(1,6-diazaspiro [3.4] octan-6-yl) quinoline; Attorney Docket No.: 185992002240 2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(2,7-diazaspiro [4.4] nonan-2-yl) quinoline; 4-(hexahydropyrrolo[3,4-c] pyrrol-2(1H)-yl)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline; 4-(3,6-diazabicyclo [3.2.0] heptan-3-yl)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline; 4-(3,6-diazabicyclo [3.2.0] heptan-6-yl)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline; 2-(6-fluoro-7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-2,7- diazaspiro [4.5] decane; 2-amino-1-(4-(4-(7-methoxy-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-2-yl) phenyl) piperazin-1-yl) propan-1-one; 4-(1,4-diazepan-1-yl)-6-fluoro-7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline; 2-amino-1-(4-(4-(7-methoxy-4-(3-methoxypyrrolidin-1-yl) quinolin-2-yl) phenyl) piperazin-1-yl) propan-1-one; 2-amino-1-(4-(5-(7-(dimethylamino)-4-(3-methoxypyrrolidin-1-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl) propan-1-one; ethyl (2-(6-(methylamino) pyridin-3-yl)-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin- 7-yl) carbamate; 2-amino-N-(4-(6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2-yl) phenyl)-3-methylbutanamide; 2-amino-1-(4-(5-(6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl)-2-methylpropan-1-one; 5-[4-(2, 9-diazaspiro[4.5]decan-2-yl) -7-methoxy-2-quinolyl]-N, N-dimethyl-pyridin- 2-amine; 2-(4-(piperazin-1-yl) phenyl)-4-(pyrrolidin-1-yl) quinoline; (1-(2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) pyrrolidin-3-yl) methanol; (1-(6-amino-7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) pyrrolidin- 3-yl) methanol; 2-amino-1-(5-(6-fluoro-7-methoxy-4-(2,7-diazaspiro[4.5]decan-2-yl)quinolin-2- yl)pyridin-2-yl)propan-1-one; [4-[5-[4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2-quinolyl]-2-pyridyl] piperazin-1-yl]-pyrrolidin-2-yl-methanone; 2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(2,7-diazaspiro [4.4] nonan-2-yl) quinoline; 6-(2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-2-oxa-6-azaspiro [3.4] octane; Attorney Docket No.: 185992002240 2-((5-(7-methoxy-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-2-yl) pyridin-2-yl) oxy)-N-methylethan-1-amine; 2-amino-1-(4-(5-(6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)pyridin-2-yl)piperazin-1-yl)propan-1-one; 2-amino-1-[5-[4-(2,9-diazaspiro [4.5]decan-2-yl)-7-(dimethylamino)-6-fluoro-2- quinolyl]-2-pyridyl]propan-1-one; 2-((5-(6-fluoro-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2-yl)pyridin-2- yl)oxy)-N-methylethan-1-amine; 2-((5-(6,7-difluoro-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2-yl)pyridin- 2-yl)oxy)-N-methylethan-1-amine; N-[4-[4-(2, 9-diazaspiro[4.5]decan-2-yl) -6-fluoro-7-methoxy-2- quinolyl]phenyl]acetamide; 5-[7-chloro-4-(2, 9-diazaspiro[4.5]decan-2-yl)-2-quinolyl]-N-methyl-pyridin-2-amine; 2-(6-piperazin-1-yl-3-pyridyl)-4-[3,6-diazabicyclo [3.2.0] heptan-6-yl] quinoline; 2-amino-1-(4-(5-(4-(3-(hydroxymethyl) pyrrolidin-1-yl)-7-methoxyquinolin-2-yl) pyridin-2-yl) piperazin-1-yl)-3-methylbutan-1-one; 2-amino-1-[4-[5-[4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2-quinolyl]-2- pyridyl] piperazin-1-yl]-4-methyl-pentan-1-one; and 2-(azetidin-1-yl)-5-[4-(2,9-diazaspiro [4.5]decan-2-yl)-7-methoxy-2-quinolyl]thiazole. In some embodiments, the compound is selected from the group consisting of 1-(4-(5-(6,7-dimethoxy-4-(pyrrolidin-1-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1- yl) ethan-1-one; (1-(2-(6-(azetidin-1-yl) pyridin-3-yl)-6-fluoro-7-methoxyquinolin-4-yl) pyrrolidin-3- yl) methanol; 2-(4-(5-(6-fluoro-4-(3-(hydroxymethyl) pyrrolidin-1-yl)-7-methoxyquinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-ol; (1-(2-(2-(azetidin-1-yl) thiazol-5-yl)-6-fluoro-7-methoxyquinolin-4-yl) pyrrolidin-3- yl) methanol; (1-(2-(6-(azetidin-1-yl) pyridin-3-yl)-7-(dimethylamino)-6-fluoroquinolin-4-yl) pyrrolidin-3-yl) methanol; 2-(2-(6-(dimethylamino) pyridin-3-yl)-7-methoxyquinolin-4-yl) octahydro-6H- pyrrolo[3,4-c] pyridin-6-one; Attorney Docket No.: 185992002240 6,7-dimethoxy-2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(pyrrolidin-1-yl) quinoline; 2-(4-(5-(6,7-dimethoxy-4-(pyrrolidin-1-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1- yl) ethan-1-ol; 1-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-3-methylpyrrolidin-3- ol; (1-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) pyrrolidin-3-yl) methanol; 2-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-2,7-diazaspiro [4.5] decane; 4-(2-methylpyrrolidin-1-yl)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline; 2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(pyrrolidin-1-yl) quinoline; 2-(2-(6-(azetidin-3-yl) pyridin-3-yl)-7-methoxyquinolin-4-yl)-2,7-diazaspiro [4.5] decane; 6-methoxy-4-(3-methoxypyrrolidin-1-yl)-N, N-dimethyl-2-(4-(2-(methylamino) ethoxy) phenyl) quinolin-7-amine; 4-(3-methoxypyrrolidin-1-yl)-N, N-dimethyl-2-(6-(2-(methylamino) ethoxy) pyridin- 3-yl) quinolin-7-amine; 2-(6-fluoro-7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-2,7- diazaspiro [4.5] decane; (1-(6-fluoro-7-methoxy-2-(6-(methylamino) pyridin-3-yl) quinolin-4-yl) pyrrolidin-3- yl) methanol; 5-(6-fluoro-7-methoxy-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-2-yl)-N- methylpyridin-2-amine; 2-(6-(piperazin-1-yl)pyridin-3-yl)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinoline; (1-(2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) pyrrolidin-3-yl) methanol; 2-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-7-methyl-2,7- diazaspiro [4.5] decane; 7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(2,6-diazaspiro [3.4] octan-6-yl) quinoline; 2-(7-methoxy-2-(4-(piperazin-1-yl) phenyl) quinolin-4-yl)-2,7-diazaspiro [4.5] decane; 2-(4-(7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2-yl) phenoxy)-N-methylethan-1-amine; Attorney Docket No.: 185992002240 6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl)-2-(6-(piperazin-1- yl) pyridin-3-yl) quinoline; 6-fluoro-N, N-dimethyl-2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-7-amine; 2-(4-(6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2-yl) phenoxy)-N-methylethan-1-amine; 5-(7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2-yl)-N, N- dimethylpyridin-2-amine; (1-(2-(6-(2-(cyclopropylamino) ethoxy) pyridin-3-yl)-6-fluoro-7-methoxyquinolin-4- yl) pyrrolidin-3-yl) methanol; 2-amino-1-(5-(6-fluoro-4-(3-(hydroxymethyl) pyrrolidin-1-yl)-7-methoxyquinolin-2- yl) pyridin-2-yl) propan-1-one; 2-(2-(6-(azetidin-1-yl) pyridin-3-yl)-6-fluoro-7-methoxyquinolin-4-yl)-2,7-diazaspiro [4.5] decane; 2-amino-1-(4-(5-(7-methoxy-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl) propan-1-one; 4-hexahydropyrrolo[3,4-c] pyrrol-2(1H)-yl)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline; 1-(4-(5-(4-(3,6-diazabicyclo [3.2.0] heptan-3-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl)-2-aminopropan-1-one; 2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(1,6-diazaspiro [3.4] octan-6-yl) quinoline; 2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(2,7-diazaspiro [4.4] nonan-2-yl) quinoline; 4-(3,6-diazabicyclo [3.2.0] heptan-6-yl)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline; 4-(3,6-diazabicyclo [3.2.0] heptan-3-yl)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline; 2-(6-fluoro-7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-2,7- diazaspiro [4.5] decane; 2-amino-1-(4-(4-(7-methoxy-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-2-yl) phenyl) piperazin-1-yl) propan-1-one; 4-(1,4-diazepan-1-yl)-6-fluoro-7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline; 2-amino-1-(4-(4-(7-methoxy-4-(3-methoxypyrrolidin-1-yl) quinolin-2-yl) phenyl) piperazin-1-yl) propan-1-one; Attorney Docket No.: 185992002240 2-amino-1-(4-(5-(7-(dimethylamino)-4-(3-methoxypyrrolidin-1-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl) propan-1-one; ethyl (2-(6-(methylamino) pyridin-3-yl)-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin- 7-yl) carbamate; 2-amino-N-(4-(6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2-yl) phenyl)-3-methylbutanamide; 2-amino-1-(4-(5-(6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl)-2-methylpropan-1-one; 5-[4-(2, 9-diazaspiro[4.5]decan-2-yl) -7-methoxy-2-quinolyl]-N, N-dimethyl-pyridin- 2-amine; 2-(4-(piperazin-1-yl) phenyl)-4-(pyrrolidin-1-yl) quinoline; (1-(2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) pyrrolidin-3-yl) methanol; (1-(6-amino-7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) pyrrolidin- 3-yl) methanol; 2-amino-1-(5-(6-fluoro-7-methoxy-4-(2,7-diazaspiro[4.5]decan-2-yl)quinolin-2- yl)pyridin-2-yl)propan-1-one; [4-[5-[4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2-quinolyl]-2-pyridyl] piperazin-1-yl]-pyrrolidin-2-yl-methanone; 2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(2,7-diazaspiro [4.4] nonan-2-yl) quinoline; 6-(2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-2-oxa-6-azaspiro [3.4] octane; 2-((5-(7-methoxy-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-2-yl) pyridin-2-yl) oxy)-N-methylethan-1-amine; 2-amino-1-(4-(5-(6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)pyridin-2-yl)piperazin-1-yl)propan-1-one; 2-amino-1-[5-[4-(2,9-diazaspiro [4.5]decan-2-yl)-7-(dimethylamino)-6-fluoro-2- quinolyl]-2-pyridyl]propan-1-one; 2-((5-(6-fluoro-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2-yl)pyridin-2- yl)oxy)-N-methylethan-1-amine; 2-((5-(6,7-difluoro-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2-yl)pyridin- 2-yl)oxy)-N-methylethan-1-amine; N-[4-[4-(2, 9-diazaspiro[4.5]decan-2-yl) -6-fluoro-7-methoxy-2- quinolyl]phenyl]acetamide; 5-[7-chloro-4-(2, 9-diazaspiro[4.5]decan-2-yl)-2-quinolyl]-N-methyl-pyridin-2-amine; Attorney Docket No.: 185992002240 2-(6-piperazin-1-yl-3-pyridyl)-4-[3,6-diazabicyclo [3.2.0] heptan-6-yl] quinoline; 2-amino-1-(4-(5-(4-(3-(hydroxymethyl) pyrrolidin-1-yl)-7-methoxyquinolin-2-yl) pyridin-2-yl) piperazin-1-yl)-3-methylbutan-1-one; 2-amino-1-[4-[5-[4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2-quinolyl]-2- pyridyl] piperazin-1-yl]-4-methyl-pentan-1-one; 2-(azetidin-1-yl)-5-[4-(2,9-diazaspiro [4.5]decan-2-yl)-7-methoxy-2- quinolyl]thiazole; 4-(3-methoxypyrrolidin-1-yl)-N,N-dimethyl-2-(2-(piperazin-1-yl)thiazol-5- yl)quinolin-7-amine; 2-(4-(5-(6-fluoro-4-(3-(hydroxymethyl)pyrrolidin-1-yl)-7-methoxyquinolin-2- yl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol; 2-amino-1-(5-(6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)pyridin-2-yl)propan-1-one; 2-amino-1-(4-(5-(4-(3-(hydroxymethyl)pyrrolidin-1-yl)-7-methoxyquinolin-2- yl)pyridin-2-yl)piperazin-1-yl)propan-1-one; 2-(4-(6-fluoro-7-(methoxy-d3)-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin- 2-yl)phenoxy)-N-methylethan-1-amine; (1-(2-(6-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridin-3-yl)-7- methoxyquinolin-4-yl)pyrrolidin-3-yl)methanol; (1-(7-(dimethylamino)-2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4-yl)pyrrolidin-3- yl)methanol; 2-(7-(methoxy-d3)-2-(4-(piperazin-1-yl)phenyl)quinolin-4-yl)-2,7- diazaspiro[4.5]decane; (1-(7-methoxy-2-(6-(2-(methylamino)ethoxy)pyridin-3-yl)quinolin-4-yl)pyrrolidin-3- yl)methanol; 2-amino-N-(5-(6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)pyridin-2-yl)-N-methylpropanamide; ethyl (2-(2-(azetidin-1-yl)thiazol-5-yl)-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-7-yl)carbamate; 2-amino-1-(4-(7-(methoxy-d3)-4-(2,7-diazaspiro[4.5]decan-2-yl)quinolin-2- yl)phenyl)propan-1-one; 2-amino-1-(4-(7-(methoxy-d3)-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin- 2-yl)phenyl)propan-1-one; Attorney Docket No.: 185992002240 2-amino-1-(4-(6-fluoro-7-(methoxy-d3)-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)phenyl)propan-1-one; 2-amino-1-(4-(7-(dimethylamino)-6-fluoro-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)phenyl)propan-1-one; 2-(4-(6-fluoro-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-7-(pent-4-yn-1- yloxy)quinolin-2-yl)phenoxy)-N-methylethan-1-amine; 2-(6-(azetidin-1-yl)pyridin-3-yl)-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c]pyridin- 2-yl)quinoline; 2-(6-(azetidin-1-yl)pyridin-3-yl)-6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinoline; 2-(4-(6-fluoro-7-methoxy-4-(2,7-diazaspiro[4.5]decan-2-yl)quinolin-2-yl)phenoxy)- N-methylethan-1-amine; 2-(2-(4-(azetidin-1-yl)phenyl)-6-fluoro-7-methoxyquinolin-4-yl)-2,7- diazaspiro[4.5]decane; 2-amino-N-(5-(6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)pyridin-2-yl)-2-methylpropanamide; (1-(2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)pyrrolidin-3-yl)methanol; (1-(7-methoxy-2-(4-(piperazin-1-yl)phenyl)quinolin-4-yl)pyrrolidin-3-yl)methanol; 4-(3-methoxypyrrolidin-1-yl)-N,N-dimethyl-2-(4-(2- (methylamino)ethoxy)phenyl)quinolin-7-amine; 2-(6-(piperazin-1-yl)pyridin-3-yl)-4-(2,6-diazaspiro[3.4]octan-2-yl)quinoline; 2-amino-N-(5-(6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)pyridin-2-yl)propanamide; 2-(2-(6-(azetidin-1-yl)pyridin-3-yl)-6-fluoro-7-methoxyquinolin-4-yl)-2,7- diazaspiro[4.5]decan-8-one; (1-(6-fluoro-7-methoxy-2-(6-(methyl(2-(methylamino)ethyl)amino)pyridin-3- yl)quinolin-4-yl)pyrrolidin-3-yl)methanol; (1-(6-fluoro-7-methoxy-2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4-yl)pyrrolidin-3- yl)methanol; [1-[7-(dimethylamino)-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4- quinolyl]pyrrolidin-3-yl]methanol; [1-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]pyrrolidin- 3-yl]methanol; Attorney Docket No.: 185992002240 [1-[6-fluoro-2-[4-[2-(methylamino)ethoxy]phenyl]-7-(trideuteriomethoxy)-4- quinolyl]pyrrolidin-3-yl]methanol; 2-[4-[4-(2,9-diazaspiro[4.5]decan-2-yl)-6-fluoro-7-(trideuteriomethoxy)-2- quinolyl]phenoxy]-N-methyl-ethanamine; 2-[4-[6-fluoro-7-methoxy-4-(9-methyl-2,9-diazaspiro[4.5]decan-2-yl)-2- quinolyl]phenoxy]-N-methyl-ethanamine; 5-[7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)-2- quinolyl]-N,N-dimethyl-pyridin-2-amine; 7-[7-methoxy-2-(4-piperazin-1-ylphenyl)-4-quinolyl]-2-oxa-7-azaspiro[3.4]octane; [1-[6-fluoro-7-methoxy-2-[5-[2-(methylamino)ethoxy]-2-pyridyl]-4- quinolyl]pyrrolidin-3-yl]methanol; [1-[7-chloro-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]pyrrolidin-3- yl]methanol; 2-[2-[6-(dimethylamino)-3-pyridyl]-7-methoxy-4-quinolyl]-3,3a,5,6,7,7a-hexahydro- 1H-pyrrolo[3,4-c]pyridin-4-one; 2-(2-(4-(azetidin-3-yloxy)phenyl)-7-methoxyquinolin-4-yl)octahydro-4H-pyrrolo[3,4- c]pyridin-4-one; 2-[4-[7-methoxy-4-(9-methyl-2,9-diazaspiro[4.5]decan-2-yl)-2-quinolyl]phenoxy]-N- methyl-acetamide; 2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-2,7- diazaspiro[4.5]decan-6-one; 2-[4-[4-(2,9-diazaspiro[4.5]decan-2-yl)-7-methoxy-2-quinolyl]phenoxy]-N-methyl- acetamide; [1-[7-(dimethylamino)-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]pyrrolidin-3- yl]methanol; ethyl N-[4-[3-(hydroxymethyl)pyrrolidin-1-yl]-2-[4-[2-(methylamino)ethoxy]phenyl]- 7-quinolyl]carbamate; [1-[2-(4-piperazin-1-ylphenyl)-4-quinolyl]pyrrolidin-3-yl]methanol; [1-[7-methoxy-2-(4-piperazin-1-ylphenyl)-4-quinolyl]azetidin-3-yl]methanol; [1-[7-[2-(dimethylamino)ethoxy]-2-(4-pyrrolidin-1-ylphenyl)-4-quinolyl]pyrrolidin-3- yl]methanol; Attorney Docket No.: 185992002240 [1-[7-(dimethylamino)-2-[4-(methylamino)phenyl]-4-quinolyl]pyrrolidin-3- yl]methanol; N,N-dimethyl-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-(2-oxa-7- azaspiro[3.4]octan-7-yl)quinolin-7-amine; N,N-dimethyl-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)-2- [6-[2-(methylamino)ethoxy]-3-pyridyl]quinolin-7-amine; N,N-dimethyl-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-pyrrolidin-1-yl-quinolin-7- amine; 2-(4-(4-(3,3-difluoro-4-methoxypyrrolidin-1-yl)-7-methoxyquinolin-2-yl)phenoxy)- N-methylethan-1-amine; [1-[7-(dimethylamino)-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-quinolyl]azetidin- 3-yl]methanol; 2-[[5-[7-methoxy-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)-2-quinolyl]-2-pyridyl]oxy]-N- methyl-ethanamine; N,N-dimethyl-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-(6-methyl-2,6- diazaspiro[3.3]heptan-2-yl)quinolin-7-amine; 2-[4-[7-methoxy-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)-2-quinolyl]phenoxy]-N-methyl- ethanamine; 7-[2-(6-piperazin-1-yl-3-pyridyl)-4-quinolyl]-2λ6-thia-7-azaspiro[3.4]octane 2,2- dioxide; N-methyl-2-[[5-[7-morpholino-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)-2-quinolyl]-2- pyridyl]oxy]ethanamine; [1-[7-(dimethylamino)-2-[5-[2-(methylamino)ethoxy]-2-pyridyl]-4- quinolyl]pyrrolidin-3-yl]methanol; 2-(5-methoxy-2-pyridyl)-N,N-dimethyl-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)quinolin- 7-amine; [1-[2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-7-morpholino-4-quinolyl]pyrrolidin-3- yl]methanol; N,N-dimethyl-2-[5-[2-(methylamino)ethoxy]-2-pyridyl]-4-(2-oxa-7- azaspiro[3.4]octan-7-yl)quinolin-7-amine; N,N-dimethyl-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-(7-methyl-2,7- diazaspiro[4.4]nonan-2-yl)quinolin-7-amine; 7-methoxy-4-(3-methoxypyrrolidin-1-yl)-2-(4-piperazin-1-ylphenyl)quinoline; Attorney Docket No.: 185992002240 ethyl N-[4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)-2-[6- (methylamino)-3-pyridyl]-7-quinolyl]carbamate; 4-(3-methoxypyrrolidin-1-yl)-N,N-dimethyl-2-(6-piperazin-1-yl-3-pyridyl)quinolin-7- amine; [1-[7-(dimethylamino)-2-(5-methoxy-2-pyridyl)-4-quinolyl]pyrrolidin-3-yl]methanol; N-methyl-1-[1-[2-(6-piperazin-1-yl-3-pyridyl)-4-quinolyl]azetidin-3-yl]methanamine; [1-[7-methoxy-2-(5-piperazin-1-yl-2-pyridyl)-4-quinolyl]pyrrolidin-3-yl]methanol; 7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)-2-(4- piperazin-1-ylphenyl)quinoline; N,N-dimethyl-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)-2- [4-[2-(methylamino)ethoxy]phenyl]quinolin-7-amine; N-methyl-2-[[6-[7-morpholino-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)-2-quinolyl]-3- pyridyl]oxy]ethanamine; N,N-dimethyl-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-[3- (trifluoromethoxy)pyrrolidin-1-yl]quinolin-7-amine; 4-(3-ethoxypyrrolidin-1-yl)-N,N-dimethyl-2-[6-[2-(methylamino)ethoxy]-3- pyridyl]quinolin-7-amine; 2-[[5-[4-(3-methoxypyrrolidin-1-yl)-7-pyrrolidin-1-yl-2-quinolyl]-2-pyridyl]oxy]-N- methyl-ethanamine; 4-(3-methoxypyrrolidin-1-yl)-N,N-dimethyl-2-[6-(2-pyrrolidin-1-ylethoxy)-3- pyridyl]quinolin-7-amine; 2-[[5-[4-(3-methoxypyrrolidin-1-yl)-7-morpholino-2-quinolyl]-2-pyridyl]oxy]-N- methyl-ethanamine; [1-[6-fluoro-7-methoxy-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4- quinolyl]pyrrolidin-3-yl]methanol; 7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)-2-(5- pyrrolidin-1-yl-2-pyridyl)quinoline; 2-[[5-[6-fluoro-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4- c]pyridin-2-yl)-2-quinolyl]-2-pyridyl]oxy]-N-methyl-ethanamine; 4-(1,3,3a,4,5,6,7,7a-octahydropyrrolo[3,4-c]pyridin-2-yl)-7-methoxy-2-(6-pyrrolidin- 1-yl-3-pyridyl)quinoline; 6-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4- yl)octahydropyrrolo[3,4-e][1,2]thiazine 1,1-dioxide; Attorney Docket No.: 185992002240 1-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 6-fluoro-N,N-dimethyl-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-(7-methyl-2,7- diazaspiro[4.4]nonan-2-yl)quinolin-7-amine; N-methyl-1-[1-[2-(6-piperazin-1-yl-3-pyridyl)-4-quinolyl]pyrrolidin-3- yl]methanamine; 4-[3-(difluoromethoxy)pyrrolidin-1-yl]-N,N-dimethyl-2-[6-[2-(methylamino)ethoxy]- 3-pyridyl]quinolin-7-amine; 2-[7-methoxy-2-(6-piperazin-1-yl-3-pyridyl)-4-quinolyl]-3,3a,5,6,7,7a-hexahydro-1H- pyrrolo[3,4-c]pyridin-4-one; 2-[[5-[7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2- yl)-2-quinolyl]-2-pyridyl]oxy]-N-methyl-ethanamine; 2-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-2,7- diazaspiro[4.5]decan-6-one; 5-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]- 1,2,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-3-one; 2-[[5-[4-(2,2-dioxo-2λ6-thia-7-azaspiro[3.4]octan-7-yl)-6-fluoro-7-methoxy-2- quinolyl]-2-pyridyl]oxy]-N-methyl-ethanamine; 2-[4-[4-(2,2-dioxo-2λ6-thia-7-azaspiro[3.4]octan-7-yl)-6-fluoro-7-methoxy-2- quinolyl]phenoxy]-N-methyl-ethanamine; N'-[5-[6-fluoro-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4- c]pyridin-2-yl)-2-quinolyl]-2-pyridyl]-N,N'-dimethyl-ethane-1,2-diamine; 2-[6-fluoro-7-methoxy-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[4-[6-fluoro-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4- c]pyridin-2-yl)-2-quinolyl]phenoxy]-N-methyl-ethanamine; 2-[2-[6-(azetidin-1-yl)-3-pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-5-methyl- 1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; 2-[6-fluoro-7-methoxy-2-(6-pyrrolidin-1-yl-3-pyridyl)-4-quinolyl]-5-methyl- 1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; Attorney Docket No.: 185992002240 2-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-70methyl- 1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; 2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-5-methyl- 1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; 2-[6-fluoro-7-methoxy-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-quinolyl]-5- methyl-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; 2-[2-[4-(azetidin-1-yl)phenyl]-6-fluoro-7-methoxy-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[2-[6-(dimethylamino)-3-pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-5-methyl- 1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; N-[4-[4-(2,2-dioxo-2λ6-thia-7-azaspiro[3.4]octan-7-yl)-6-fluoro-2-quinolyl]phenyl]- 2-pyrrolidin-1-yl-acetamide; 1-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-N,N- dimethyl-pyrrolidine-3-carboxamide; 2-[7-(dimethylamino)-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-quinolyl]-5- methyl-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; 7-[2-[6-(azetidin-1-yl)-3-pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-2λ6-thia-7- azaspiro[4.4]nonane 2,2-dioxide; 2-[4-[4-(2,2-dioxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-c]pyrrol-5-yl)-6-fluoro-7- methoxy-2-quinolyl]phenoxy]-N-methyl-ethanamine; 6-[6-fluoro-7-methoxy-2-(6-pyrrolidin-1-yl-3-pyridyl)-4-quinolyl]-2λ6-thia-6- azaspiro[3.3]heptane 2,2-dioxide; 2-[2-[4-(azetidin-3-yloxy)phenyl]-6-fluoro-7-methoxy-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[6-fluoro-7-methoxy-2-(4-pyrrolidin-3-yloxyphenyl)-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 1-[6-fluoro-7-methoxy-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-quinolyl]-N- methyl-pyrrolidine-3-carboxamide; 2-[6-fluoro-7-methoxy-2-[4-[pyrrolidin-3-yl]oxyphenyl]-4-quinolyl]-5-methyl- 1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; 7-[2-[6-(azetidin-1-yl)-3-pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-2λ6-thia-3,7- diazaspiro[4.4]nonane 2,2-dioxide; Attorney Docket No.: 185992002240 6-[2-[6-(azetidin-1-yl)-3-pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-2-methyl- 3,4,4a,5,7,7a-hexahydropyrrolo[3,4-e]thiazine 1,1-dioxide; 2-[6-fluoro-7-methoxy-2-[4-[pyrrolidin-3-yl]oxyphenyl]-4-quinolyl]-5-methyl- 1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; 2-[4-[4-(7,7-difluoro-5-methyl-1,3,3a,4,6,7a-hexahydropyrrolo[3,4-c]pyridin-2-yl)-6- fluoro-7-methoxy-2-quinolyl]phenoxy]-N-methyl-ethanamine; 2-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-6-fluoro-7-methoxy-4-(5-methyl- 3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)quinoline; 2-[6-(1,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-6-fluoro-7-methoxy-4-(5-methyl- 3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)quinoline; 2-[6-(azetidin-3-ylmethoxy)-3-pyridyl]-6-fluoro-7-methoxy-4-(5-methyl- 3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)quinoline; 2-[6-(azetidin-2-ylmethoxy)-3-pyridyl]-6-fluoro-7-methoxy-4-(5-methyl- 3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)quinoline; 2-[4-(azetidin-3-yloxy)phenyl]-6-fluoro-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)quinoline; 6-fluoro-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin- 2-yl)-2-(4-pyrrolidin-3-yloxyphenyl)quinoline; 2-[4-[6-fluoro-7-methoxy-4-(8-methyl-2,8-diazaspiro[3.5]nonan-2-yl)-2- quinolyl]phenoxy]-N-methyl-ethanamine; 2-[4-[6-fluoro-7-methoxy-4-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)-2- quinolyl]phenoxy]-N-methyl-ethanamine; 2-[[5-[6-fluoro-7-methoxy-4-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)-2-quinolyl]-2- pyridyl]oxy]-N-methyl-ethanamine; 2-[6-fluoro-7-methoxy-2-(6-pyrrolidin-1-yl-3-pyridyl)-4-quinolyl]-9-methyl-2,6,9- triazaspiro[4.5]decan-8-one; 2-[4-[4-(2,2-dioxo-2λ6-thia-7-azaspiro[3.4]octan-7-yl)-6,7-difluoro-2- quinolyl]phenoxy]-N-methyl-ethanamine; 2-[6,7-difluoro-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 7-[2-[6-(azetidin-1-yl)-3-pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-3-methyl-2λ6-thia- 3,7-diazaspiro[4.4]nonane 2,2-dioxide; Attorney Docket No.: 185992002240 6-[6-fluoro-7-methoxy-2-(6-pyrrolidin-1-yl-3-pyridyl)-4-quinolyl]-2-methyl-2,6- diazaspiro[3.4]octan-3-one; 2-[[5-[4-(7,7-difluoro-5-methyl-1,3,3a,4,6,7a-hexahydropyrrolo[3,4-c]pyridin-2-yl)-6- fluoro-7-methoxy-2-quinolyl]-2-pyridyl]oxy]-N-methyl-ethanamine; 4-[5-(2,2-difluoroethyl)-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl]-6- fluoro-7-methoxy-2-(6-pyrrolidin-1-yl-3-pyridyl)quinoline; 2-[6-fluoro-7-methoxy-2-(6-pyrrolidin-1-yl-3-pyridyl)-4-quinolyl]-9-methyl-2,6,9- triazaspiro[4.5]decan-7-one; 2-[4-[6-fluoro-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4- c]pyridin-2-yl)-2-quinolyl]phenyl]sulfanyl-N-methyl-ethanamine; 6-fluoro-2-[4-(1H-imidazol-4-yloxy)phenyl]-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)quinoline; 2-[6-fluoro-7-methoxy-2-(6-piperazin-1-yl-3-pyridyl)-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[4-[4-(2,2-dioxo-2λ6-thia-7-azaspiro[3.4]octan-7-yl)-2-quinolyl]phenoxy]-N- methyl-ethanamine; 6-fluoro-4-(3-methoxypyrrolidin-1-yl)-N,N-dimethyl-2-[4-[2- (methylamino)ethoxy]phenyl]quinolin-7-amine; 2-[[5-(6-fluoro-7-methoxy-4-pyrrolidin-1-yl-2-quinolyl)-2-pyridyl]oxy]-N-methyl- ethanamine; 2-[4-[4-(2,2-dioxo-2λ6-thia-7-azaspiro[3.4]octan-7-yl)-6-fluoro-7-pent-4-ynoxy-2- quinolyl]phenoxy]-N-methyl-ethanamine; 1-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]pyrrolidin- 3-one; 2-[4-[4-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-6-fluoro-7-methoxy-2- quinolyl]phenoxy]-N-methyl-ethanamine; 2-[4-[4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-6-fluoro-7-methoxy-2- quinolyl]phenoxy]-N-methyl-ethanamine; 2-[[5-[4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-6-fluoro-7-methoxy-2- quinolyl]-2-pyridyl]oxy]-N-methyl-ethanamine; 7-[6-fluoro-2-[4-(1H-imidazol-4-yloxy)phenyl]-7-methoxy-4-quinolyl]-2λ6-thia-7- azaspiro[3.4]octane 2,2-dioxide; Attorney Docket No.: 185992002240 5-[6-fluoro-7-methoxy-2-(4-pyrrolidin-1-ylphenyl)-4-quinolyl]-1,3,3a,4,6,6a- hexahydrothieno[3,4-c]pyrrole 2,2-dioxide; 6-fluoro-N,N-dimethyl-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4- c]pyridin-2-yl)-2-[4-[2-(methylamino)ethoxy]phenyl]quinolin-7-amine; 6-fluoro-N,N-dimethyl-2-[4-[2-(methylamino)ethoxy]phenyl]-4-(2-oxa-7- azaspiro[3.4]octan-7-yl)quinolin-7-amine; 2-[4-[6-fluoro-7-methoxy-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)-2-quinolyl]phenoxy]- N-methyl-ethanamine; 6-fluoro-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin- 2-yl)-2-(4-piperazin-1-ylphenyl)quinoline; 6-fluoro-N,N-dimethyl-2-[4-[2-(methylamino)ethoxy]phenyl]-4-(7-methyl-2,7- diazaspiro[4.4]nonan-2-yl)quinolin-7-amine; 2-[2-[6-(azetidin-1-yl)-3-pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-3,3a,4,6,7,7a- hexahydro-1H-thiopyrano[3,4-c]pyrrole 5,5-dioxide; 2-[[6-[4-(2,9-diazaspiro[4.5]decan-2-yl)-6-fluoro-7-(trideuteriomethoxy)-2-quinolyl]- 3-pyridyl]oxy]-N-methyl-ethanamine; [1-[6-fluoro-2-[5-[2-(methylamino)ethoxy]-2-pyridyl]-7-(trideuteriomethoxy)-4- quinolyl]pyrrolidin-3-yl]methanol; 2-[[5-[4-(2,2-dioxo-2λ6-thia-7-azaspiro[3.4]octan-7-yl)-6-fluoro-7-methoxy-2- quinolyl]-2-pyridyl]oxy]-N,N-dimethyl-ethanamine; 2-[4-[6-fluoro-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)-7- (trideuteriomethoxy)-2-quinolyl]phenoxy]-N-methyl-ethanamine; 6-fluoro-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin- 2-yl)-2-(6-piperazin-1-yl-3-pyridyl)quinoline; 5-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]- 1,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-2-one; 2-[[5-[4-(9,9-difluoro-7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-6-fluoro-7-methoxy- 2-quinolyl]-2-pyridyl]oxy]-N-methyl-ethanamine; 2-[4-[4-(9,9-difluoro-7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-6-fluoro-7-methoxy-2- quinolyl]phenoxy]-N-methyl-ethanamine; 2-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-5-methyl- 1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; Attorney Docket No.: 185992002240 2-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-6-fluoro-7-methoxy-4-quinolyl]-5-methyl- 1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; 2-[4-[4-(2,2-dioxo-2λ6-thia-7-azaspiro[3.4]octan-7-yl)-6-fluoro-7-methoxy-2- quinolyl]phenoxy]-N,N-dimethyl-ethanamine; 5-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-2-methyl- 3a,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-3-one; 2-[2-[4-(azetidin-3-yloxy)phenyl]-6-fluoro-7-methoxy-4-quinolyl]-5-methyl- 1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; 2,2-difluoro-N-[2-[4-[6-fluoro-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H- pyrrolo[3,4-c]pyridin-2-yl)-2-quinolyl]phenoxy]ethyl]ethanamine; 6-fluoro-N,N-dimethyl-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-(2-methyl-2,6- diazaspiro[3.4]octan-6-yl)quinolin-7-amine; 2-[[5-[6-fluoro-7-methoxy-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)-2-quinolyl]-2- pyridyl]oxy]-N-methyl-ethanamine; 2-[4-[6-fluoro-7-methoxy-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-2- quinolyl]phenoxy]-N-methyl-ethanamine; 2-[6-fluoro-7-methoxy-2-[4-[2-24(methylamino)ethoxy]phenyl]-4-quinolyl]-6- methyl-2,6-diazaspiro[3.5]nonan-5-one; 4,4-difluoro-7-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4- quinolyl]-2-methyl-2,7-diazaspiro[4.4]nonan-1-one; 2-(4-(4-(3,3-difluoro-4-methoxypyrrolidin-1-yl)-7-methoxyquinolin-2-yl)phenoxy)- N-methylethan-1-amine; 2-[4-[6-fluoro-7-methoxy-4-(1-methyl-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrol- 4-yl)-2-quinolyl]phenoxy]-N-methyl-ethanamine; 3-[4-[6-fluoro-7-methoxy-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-2- quinolyl]phenoxy]-N-methyl-propan-1-amine; 2-[4-(azetidin-3-ylmethoxy)phenyl]-6-fluoro-7-methoxy-4-(7-methyl-2,7- diazaspiro[4.4]nonan-2-yl)quinoline; 2-[4-[4-[3-[(dimethylamino)methyl]pyrrolidin-1-yl]-6-fluoro-7-methoxy-2- quinolyl]phenoxy]-N-methyl-ethanamine; 2-[2-[4-(azetidin-3-ylmethoxy)phenyl]-6-fluoro-7-methoxy-4-quinolyl]-5-methyl- 1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; Attorney Docket No.: 185992002240 1-[5-[6-fluoro-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4- c]pyridin-2-yl)-2-quinolyl]-2-pyridyl]pyrrolidin-3-ol; 2-[6-fluoro-7-methoxy-2-(4-piperazin-1-ylphenyl)-4-quinolyl]-5-methyl- 1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; 2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-5-methyl- 1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; 2-[4-[4-[5-(2,2-difluoroethyl)-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2- yl]-7-methoxy-2-quinolyl]phenoxy]-N-methyl-ethanamine; 2-[[5-[7-methoxy-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-quinolyl]-2- pyridyl]oxy]-N-methyl-ethanamine; 2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-7-methyl-2,7- diazaspiro[4.4]nonan-8-one; 2-[4-[7-methoxy-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-quinolyl]phenoxy]-N- methyl-ethanamine; 1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 7-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-2,7- diazaspiro[4.4]nonan-1-one; 2-[4-[4-(3,3-difluoropyrrolidin-1-yl)-6-fluoro-7-methoxy-2-quinolyl]phenoxy]-N- methyl-ethanamine; 2-[4-[7-methoxy-4-(3-methyl-2,2-dioxo-2λ6-thia-3,7-diazaspiro[4.4]nonan-7-yl)-2- quinolyl]phenoxy]-N-methyl-ethanamine; 2-[4-[4-(1,3-dimethyl-2,2-dioxo-2λ6-thia-3,7-diazaspiro[4.4]nonan-7-yl)-7-methoxy- 2-quinolyl]phenoxy]-N-methyl-ethanamine; 2-[6-fluoro-7-methoxy-2-[4-(2-methoxyethoxy)phenyl]-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[6-fluoro-7-methoxy-2-[4-[2-(trideuteriomethoxy)ethoxy]phenyl]-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[1-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4- quinolyl]pyrrolidin-3-yl]-N-methyl-acetamide; 2-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-7-methoxy-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; Attorney Docket No.: 185992002240 2-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-2,7- diazaspiro[4.4]nonan-8-one; 2-[2-[4-(azetidin-3-yloxy)phenyl]-7-methoxy-4-quinolyl]-3,3a,5,6,7,7a-hexahydro- 1H-pyrrolo[3,4-c]pyridin-4-one; 2-[7-methoxy-2-[4-[pyrrolidin-3-yl]oxyphenyl]-4-quinolyl]-3,3a,5,6,7,7a-hexahydro- 1H-pyrrolo[3,4-c]pyridin-4-one; N-methyl-2-[4-[7-morpholino-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)-2- quinolyl]phenoxy]ethanamine; 2-[2-[4-[2-(methylamino)ethoxy]phenyl]-7-(trideuteriomethoxy)-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[7-methoxy-2-[5-[2-(methylamino)ethoxy]-2-pyridyl]-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]pyrrolidin-3-yl]- N-methyl-acetamide; 2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-2,7- diazaspiro[4.4]nonan-8-one; 2-[2-[4-[2-(cyclopropylamino)ethoxy]phenyl]-7-methoxy-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[4-[7-methoxy-4-(3-methoxypyrrolidin-1-yl)-2-quinolyl]phenoxy]-N-methyl- ethanamine; 2-[7-ethoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 7-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-2,7- diazaspiro[4.4]nonan-1-one; 1-[[4-[4-(5-azaspiro[2.4]heptan-5-yl)-6-fluoro-7-methoxy-2- quinolyl]phenoxy]methyl]-N-methyl-cyclopropanamine; 2-[7-methoxy-2-[4-[[1-(methylamino)cyclopropyl]methoxy]phenyl]-4-quinolyl]-5- methyl-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; 2-[7-chloro-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 1-[4-[7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2- yl)-2-quinolyl]phenyl]pyrrolidin-3-ol; Attorney Docket No.: 185992002240 2-[7-methyl-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[7-cyclopropyl-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 5-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-1,3,3a,4,6,6a- hexahydropyrrolo[2,3-c]pyrrol-2-one; 2-[2-[4-[3-hydroxypyrrolidin-1-yl]phenyl]-7-methoxy-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 6-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-3,4,4a,5,7,7a- hexahydro-1H-pyrrolo[3,4-b]pyridin-2-one; 7-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-1,7- diazaspiro[4.4]nonan-2-one; 2-[7-(2-methoxyethoxy)-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-5-methyl- 3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-7-ol; 2-[7-(difluoromethoxy)-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[4-[7-methoxy-4-[3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]-2-quinolyl]phenoxy]- N-methyl-ethanamine; 2-[4-[4-(3,3-difluoro-4-methoxy-pyrrolidin-1-yl)-7-methoxy-2-quinolyl]phenoxy]-N- methyl-ethanamine; 2-[4-[7-methoxy-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-quinolyl]phenoxy]- N,N-dimethyl-ethanamine; 2-[8-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 2-[4-[4-[3-[(dimethylamino)methyl]pyrrolidin-1-yl]-7-methoxy-2-quinolyl]phenoxy]- N-methyl-ethanamine; 7-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-3-methyl-1,7- diazaspiro[4.4]nonan-2-one; 2-[7-methoxy-2-[4-[3-(methylamino)propoxy]phenyl]-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; Attorney Docket No.: 185992002240 2-[7-methoxy-2-[5-[2-(methylamino)ethoxy]-2-pyridyl]-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 3a-fluoro-2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]- 1,3,5,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one; 5-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-b]pyrrol-2-one; 5-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-1,2,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-3-one; 2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-2,7- diazaspiro[4.4]nonan-8-one; 3-[4-[7-methoxy-4-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)-2-quinolyl]phenoxy]-N- methyl-propan-1-amine; 2-(7-methoxy-2-(4-(piperazin-1-yl)phenyl)quinolin-4-yl)octahydro-4H-pyrrolo[3,4- c]pyridin-4-one; N-(1-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)pyrrolidin-3- yl)acetamide; 6-fluoro-7-methoxy-4-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-2-(6- (pyrrolidin-1-yl)pyridin-3-yl)quinoline; 4-(3-methoxypyrrolidin-1-yl)-N,N-dimethyl-2-(5-(2-(methylamino)ethoxy)pyridin-2- yl)quinolin-7-amine; 6-(7-methoxy-2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4-yl)-2-thia-6- azaspiro[3.4]octane 2,2-dioxide; 2-(1-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)pyrrolidin-3-yl)- N-methylacetamide; ethyl (1-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)pyrrolidin-3- yl)carbamate; 2-(7-methoxy-2-(6-(2-(methylamino)ethoxy)pyridin-3-yl)quinolin-4-yl)octahydro- 4H-pyrrolo[3,4-c]pyridin-4-one; 6-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)-2-thia-6- azaspiro[3.4]octane 2,2-dioxide; 1-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)pyrrolidine-3- carbonitrile; Attorney Docket No.: 185992002240 1-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)-N,N- dimethylpyrrolidine-3-carboxamide; 1-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)pyrrolidin-3-yl methylcarbamate; 2-(4-(7-methoxy-4-(3-((methylamino)methyl)pyrrolidin-1-yl)quinolin-2-yl)phenoxy)- N-methylethan-1-amine; 5-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)hexahydro-1H- thieno[3,4-c]pyrrole 2,2-dioxide; 2-(dimethylamino)-N-(4-(7-methoxy-4-(4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)phenyl)acetamide; 2-(2-(4-(2-(1H-pyrazol-1-yl)ethoxy)phenyl)-7-methoxyquinolin-4-yl)octahydro-4H- pyrrolo[3,4-c]pyridin-4-one; 1-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)-N,N- dimethylpyrrolidin-3-amine; 6-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)-2-thia-6- azaspiro[3.3]heptane 2,2-dioxide; 5-(6-fluoro-7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4- yl)hexahydropyrrolo[3,4-b]pyrrol-2(1H)-one; 2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one; 6-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-2-methyl-2,6- diazaspiro[3.4]octan-3-one; 2-[4-[7-methoxy-4-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)-2-quinolyl]phenoxy]-N- methyl-ethanamine; 2-[7-methoxy-2-(5-methoxy-2-pyridyl)-4-quinolyl]-3,3a,5,6,7,7a-hexahydro-1H- pyrrolo[3,4-c]pyridin-4-one; N-[[1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]pyrrolidin-3- yl]methyl]-N-methyl-acetamide; 2-[[6-[4-(2,9-diazaspiro[4.5]decan-2-yl)-6-fluoro-7-methoxy-2-quinolyl]-3- pyridyl]oxy]-N-methyl-ethanamine; N-[1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]pyrrolidin-3- yl]methanesulfonamide; Attorney Docket No.: 185992002240 1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-N,3-dimethyl- pyrrolidine-3-carboxamide; 2-(7-methoxy-2-(4-(2-(methylamino)cyclopropoxy)phenyl)quinolin-4-yl)octahydro- 4H-pyrrolo[3,4-c]pyridin-4-one; 2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-2,6- diazaspiro[3.4]octan-5-one; 2-[[1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]pyrrolidin-3- yl]amino]etanol; 1-(7-methoxy-2-(4-(3-(methylamino)cyclobutoxy)phenyl)quinolin-4-yl)-N- methylpyrrolidine-3-carboxamide; 2-[4-[7-methoxy-4-[3-(methylaminomethyl)azetidin-1-yl]-2-quinolyl]phenoxy]-N- methyl-ethanamine; N-methyl-2-[4-[4-[3-(methylaminomethyl)azetidin-1-yl]-2- quinolyl]phenoxy]ethanamine; 1-[7-methoxy-2-(4-piperazin-1-ylphenyl)-4-quinolyl]-N-methyl-pyrrolidine-3- carboxamide; 6-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-3,4,4a,5,7,7a- hexahydro-1H-pyrrolo[3,4-b]pyridin-2-one; 1-[7-methoxy-2-[4-[3-(methylamino)propyl]phenyl]-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 1-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-7-methoxy-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; [1-[7-(dimethylamino)-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]pyrrolidin- 3-yl]methanol; 1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-N-methyl- pyrrolidine-3-sulfonamide; 1-[4-[4-[3-[(dimethylamino)methyl]pyrrolidin-1-yl]-7-methoxy-2-quinolyl]phenoxy]- 3-(methylamino)propan-2-ol; 5-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-1,2,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-3-one; N-ethyl-1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]pyrrolidine- 3-carboxamide; Attorney Docket No.: 185992002240 2-[4-[7-methoxy-4-[3-morpholinopyrrolidin-1-yl]-2-quinolyl]phenoxy]-N-methyl- ethanamine; N-(2-methoxyethyl)-1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4- quinolyl]pyrrolidine-3-carboxamide; N-cyclopropyl-1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4- quinolyl]pyrrolidine-3-carboxamide; 1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-N-methyl-azetidine- 3-carboxamide; 2-[4-[4-(2,2-dioxo-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c][1,2,5]thiadiazol-5-yl)-7- methoxy-2-quinolyl]phenoxy]-N-methyl-ethanamine; 1-[2-[4-(3,3-difluorobutoxy)phenyl]-7-methoxy-4-quinolyl]-N-methyl-pyrrolidine-3- carboxamide; 4-(hydroxymethyl)-1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4- quinolyl]pyrrolidin-3-ol; 1-[7-methoxy-2-[4-(3,3,3-trifluoropropoxy)phenyl]-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 1-[7-methoxy-2-(4-morpholinophenyl)-4-quinolyl]-N-methyl-pyrrolidine-3- carboxamide; 1-[1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]pyrrolidin-3- yl]ethanone; 1-[7-methoxy-2-[4-(2-methoxyethylamino)phenyl]-4-quinolyl]-N-methyl-pyrrolidine- 3-carboxamide; 6-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-1,4,4a,5,7,7a- hexahydropyrrolo[3,4-d][1,3]oxazin-2-one; 1-[7-cyclopropyl-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 1-[7-(dimethylamino)-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 1-[7-methoxy-2-[4-(2-methylsulfinylethoxy)phenyl]-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 1-[7-methoxy-2-[4-[2-methoxyethyl(methyl)amino]phenyl]-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; Attorney Docket No.: 185992002240 1-[7-methoxy-6-methyl-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 1-[6-cyclopropyl-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-N- methyl-pyrrolidine-3-carboxamide; 1-[2-[4-[2-(cyclopropylamino)ethoxy]phenyl]-7-methoxy-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 1-[7-methoxy-2-[4-[2-(2-methoxyethylamino)ethoxy]phenyl]-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 1-[7-methoxy-2-[4-(2-morpholinoethoxy)phenyl]-4-quinolyl]-N-methyl-pyrrolidine- 3-carboxamide; N-methyl-1-[2-[4-[2-(methylamino)ethoxy]phenyl]-7-(trideuteriomethoxy)-4- quinolyl]pyrrolidine-3-carboxamide; 2-[4-[7-methoxy-4-[3-[methylsulfinyl]pyrrolidin-1-yl]-2-quinolyl]phenoxy]-N- methyl-ethanamine; 5-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]- 1,2,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-3-one; 1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 1-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 2-[4-[4-(2,2-dioxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-c]pyrrol-5-yl)-7-methoxy-2- quinolyl]phenoxy]-N,N-dimethyl-ethanamine; 7-[7-methoxy-2-(4-methoxyphenyl)-4-quinolyl]-2λ6-thia-7-azaspiro[3.4]octane 2,2- dioxide; 1-[2-[4-[2-(isopropylamino)ethoxy]phenyl]-7-methoxy-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 1-[2-[4-[2-hydroxyethyl(methyl)amino]phenyl]-7-methoxy-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 1-[2-[4-[2-(isobutylamino)ethoxy]phenyl]-7-methoxy-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; 1-[7-methoxy-2-[5-[2-(methylamino)ethoxy]-2-pyridyl]-4-quinolyl]-N-methyl- pyrrolidine-3-carboxamide; Attorney Docket No.: 185992002240 2-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)-2,6- diazaspiro[3.5]nonan-5-one; 5-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)hexahydro-1H- pyrrolo[3,4-c]isothiazole 2,2-dioxide; 1-(7-methoxy-2-(4-(2-(methylamino)propoxy)phenyl)quinolin-4-yl)-N- methylpyrrolidine-3-carboxamide; 4-(hydroxymethyl)-1-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4- yl)pyrrolidin-3-ol; 2,2,2-trifluoro-1-(1-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4- yl)pyrrolidin-3-yl)-N-methylethan-1-amine; 2,2,2-trifluoro-1-(1-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4- yl)pyrrolidin-3-yl)-N-methylethan-1-amine; N-(2-hydroxyethyl)-1-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4- yl)pyrrolidine-3-carboxamide; 5-(2-(4-(3-hydroxypyrrolidin-1-yl)phenyl)-7-methoxyquinolin-4-yl)hexahydro-1H- thieno[3,4-c]pyrrole 2,2-dioxide; 2-(4-(7-methoxy-4-(3-methoxypyrrolidin-1-yl)quinolin-2-yl)phenoxy)-N- (trifluoromethyl)ethan-1-amine; 7-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4-yl)-2-thia-3,7- diazaspiro[4.4]nonane 2,2-dioxide; 1-(4-(7-methoxy-4-(3-methoxypyrrolidin-1-yl)quinolin-2-yl)phenoxy)-3- (methylamino)propan-2-ol; and 2-(4-(7-methoxy-4-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)-N-methylethan-1-amine. PHARMACEUTICAL COMPOSITIONS Provided herein are pharmaceutical compositions comprising a compound of formula (I), or any variation or embodiment thereof or a stereoisomer or tautomer thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (IV), or (IV-A), or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, as described elsewhere herein. In some embodiments, provided herein is a pharmaceutical composition comprising (i) a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (IV), or (IV-A), or a pharmaceutically acceptable salt, hydrate, or solvate of Attorney Docket No.: 185992002240 any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a pharmaceutical composition comprising (i) a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (IV), or (IV-A), or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises a therapeutically effective amount of the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In some embodiments, the composition comprises a therapeutically effective amount of the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided herein are pharmaceutical compositions comprising (i) a compound of formula (I),
Figure imgf000187_0001
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, and (ii) one or more pharmaceutically acceptable excipients, wherein R1 and R2 are taken together with the N to which they are attached to form a saturated 4- to 5- membered monocyclic heterocyclyl, saturated 7- to 10-membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl, wherein the saturated 4- to 5-membered monocyclic heterocyclyl, saturated 7- to 9-membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl is optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, oxo, -OR 12, -N(Rx)(Ry), or -C(=O)N(R13)(R14), wherein the C1-6alkyl of R3 is optionally substituted with R3a; Ring A is 4- to 8-membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein Attorney Docket No.: 185992002240 the 4- to 8-membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 8-membered unsaturated heterocyclyl or 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, or -OR12; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-; R5 is H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), or - OR12, and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -OR12, -O-(3- to 12-membered N-containing heterocyclyl), -O-(5- to 6-membered N- containing heteroaryl), -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, - N(R13)C(=O)OR14, -OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R13)(R14), - N(R13)S(=O)2R14, -S(=O)N(R13)R14, -S(=O)2N(R13)(R14), -(C3-8cycloalkyl)N(Rx)(Ry), or 3- to 8-membered N-containing heterocyclyl, wherein the -O-(3- to 8-membered N-containing heterocyclyl), -O-(5- to 6-membered N- containing heteroaryl), or 3- to 8-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or - C(=O)OR14, and the 3- to 8-membered N-containing heterocyclyl of R6 optionally further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; R7 is H or halo; R8 and R9 are each independently H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(O)R14, - N(R13)C(O)OR14, -N(R13)C(O)N(R13)R14, -OC(O)R14, -OC(O)OR14, -OC(O)N(R13)R14, - C(O)R14, -C(O)OR14, -C(O)N(R13)(R14), C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R8 or R9 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl of R8 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R8 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; R10 is H; each R1a, R3a, R4a, R6a, or R7a is independently -OR12 or -N(Rx)(Ry); Attorney Docket No.: 185992002240 each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR 11, or -N(Rx)(Ry), wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R11 is independently H or C1-6alkyl; each R12 is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, or 5- to 10- membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, - O(C1-6alkyl), or -N(Rx)(Ry); each R13 is independently H, C1-6alkyl, or C3-8cycloalkyl; each R14 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, - N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl of R14 is optionally substituted by -OH, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, -OH, or -N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl), wherein when Ring A is phenyl, then -L-R6 is not -NH2 or -OCH3. Suitable pharmaceutically acceptable excipients may include, for example, fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, Attorney Docket No.: 185992002240 compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Examples of suitable excipients are well-known to those skilled in the art. See, e.g., Handbook of Pharmaceutical Excipients, Pharmaceutical Press (2017), which is incorporated herein by reference in its entirety. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Academic Press, 23rd ed. (2020), which is incorporated herein by reference in its entirety. METHODS OF TREATMENT Traumatic brain injury (TBI) is a risk factor for ALS as demonstrated by the significantly higher incidence of disease in professional athletes and military veterans [See, e.g., Lehman et al. Neurology 79, 1970-1974 (2012); McKee et al. J. Neuropathol. Exp. Neurol. 69, 989-929 (2010); Chio et al. Brain 128, 472-476 (2005), and Sagiraju et al. Mil. Med. 185 e501-e509 (2020), each of which is incorporated herein by reference in its entirety]. Cytoplasmic accumulation of TDP-43 has been shown in ~80% brains of patients with repeated head traumas [McKee et al. J. Neuropathol. Exp. Neurol. 69, 989-929 (2010), which is incorporated herein by reference in its entirety]. TDP-43 proteinopathy and loss-of- function has been shown to be a driver of neurodegeneration and pathology in preclinical models of brain injury and ALS [Lai et al. Cell Stem Cell 31, 519-536 (2024); Dogan et al. Acta Neuropathol Commun 11, 206 (2023); and Kahriman et al. Brain 146, 5139-5152 (2023), each of which is incorporated herein by reference in its entirety]. Neurofilament light chain (NfL) and glial fibrillary acid protein (GFAP) are prognostic neurodegeneration biomarkers for both TBI [Shahim et al. Neurology 95, e610-e622 (2020); Shahim et al. Sci Rep 6, 36791 (2016) and Abdelhak et al. Nat Rev Neuro 18, 158-172 (2022), each of which is incorporated herein by reference in its entirety] and ALS [Lu et al. Neurology 84, 2247- 2257); and Benninger et al. J Clin Neurosci 26, 75-78 (2016), each of which is incorporated herein by reference in its entirety]. In one aspect, provided is a method for treating a disease or condition mediated by TDP-43, comprising administering to an individual in need thereof a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or Attorney Docket No.: 185992002240 embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, provided is a method for treating a disease or condition mediated by TDP-43, comprising administering to an individual in need thereof a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, a therapeutically effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients is administered. In some embodiments, a therapeutically effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients is administered. In some embodiments, the methods selectively modulate TDP-43. In some embodiments, the methods reduce TDP-43 cytoplasmic inclusions, improve nuclear TDP-43 function, or reduce neurodegeneration. In some embodiments, the methods reduce TDP-43 cytoplasmic inclusions. In some embodiments, the methods improve nuclear TDP-43 function. In some embodiments, the methods reduce neurodegeneration. In some embodiments, the methods mitigate TDP-43 cytoplasmic Attorney Docket No.: 185992002240 condensates in motor neurons. In some embodiments, the motor neurons are iPSC-derived motor neurons. In some embodiments, STMN2 and POLDIP3 splicing in iPSC-derived motor neurons is restored. In some embodiments, provided herein is a method for treating a disease or condition mediated by TDP-43, comprising administering to an individual in need thereof a compound of formula (I),
Figure imgf000192_0001
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are taken together with the N to which they are attached to form a saturated 4- to 5- membered monocyclic heterocyclyl, saturated 7- to 10-membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl, wherein the saturated 4- to 5-membered monocyclic heterocyclyl, saturated 7- to 9-membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl is optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, oxo, -OR 12, -N(Rx)(Ry), or -C(=O)N(R13)(R14), wherein the C1-6alkyl of R3 is optionally substituted with R3a; Ring A is 4- to 8-membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 8-membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 8-membered unsaturated heterocyclyl or 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, or -OR 12; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-; Attorney Docket No.: 185992002240 R5 is H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), or - OR12, and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -OR12, -O-(3- to 12-membered N-containing heterocyclyl), -O-(5- to 6-membered N- containing heteroaryl), -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, - N(R13)C(=O)OR14, -OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R13)(R14), - N(R13)S(=O)2R14, -S(=O)N(R13)R14, -S(=O)2N(R13)(R14), -(C3-8cycloalkyl)N(Rx)(Ry), or 3- to 8-membered N-containing heterocyclyl, wherein the -O-(3- to 8-membered N-containing heterocyclyl), -O-(5- to 6-membered N- containing heteroaryl), or 3- to 8-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or - C(=O)OR14, and the 3- to 8-membered N-containing heterocyclyl of R6 optionally further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; R7 is H or halo; R8 and R9 are each independently H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(O)R14, - N(R13)C(O)OR14, -N(R13)C(O)N(R13)R14, -OC(O)R14, -OC(O)OR14, -OC(O)N(R13)R14, - C(O)R14, -C(O)OR14, -C(O)N(R13)(R14), C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R8 or R9 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl of R8 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R8 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; R10 is H; each R1a, R3a, R4a, R6a, or R7a is independently -OR12 or -N(Rx)(Ry); each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, or -N(Rx)(Ry), wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R11 is independently H or C1-6alkyl; Attorney Docket No.: 185992002240 each R12 is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, or 5- to 10- membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, - O(C1-6alkyl), or -N(Rx)(Ry); each R13 is independently H, C1-6alkyl, or C3-8cycloalkyl; each R14 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, - N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl of R14 is optionally substituted by -OH, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, -OH, or -N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl), wherein when Ring A is phenyl, then -L-R6 is not -NH2 or -OCH3. In some embodiments, the disease or condition is a neurological disease or condition. In some embodiments, the disease or condition is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), inclusion body myositis, Perry syndrome, corticobasal degeneration, spinocerebellar ataxia type 3, and amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or condition is traumatic brain injury (TBI). In some embodiments, the disease or condition is frontotemporal dementia (FTD). In some embodiments, the disease or condition is amyotrophic lateral sclerosis (ALS). In some variations, the amyotrophic lateral sclerosis is sporadic amyotrophic lateral sclerosis or C9ORF72 amyotrophic lateral sclerosis. Attorney Docket No.: 185992002240 In some embodiments, the individual is a human. In one aspect, provided herein is a method of reducing neurodegeneration, comprising administering to an individual in need thereof a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, provided herein is a method of reducing neurodegeneration, comprising administering to an individual in need thereof a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the individual has a neurological disease or condition. In some embodiments, the individual has a disease or condition selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), inclusion body myositis, Perry syndrome, corticobasal degeneration, spinocerebellar ataxia type 3, and amyotrophic lateral sclerosis (ALS). In some embodiments, the individual has frontotemporal dementia (FTD). In some embodiments, the individual has a traumatic brain injury or ALS. In some embodiments, the individual has a traumatic brain injury. In some embodiments, the individual has ALS. In some variations, the amyotrophic lateral sclerosis is sporadic amyotrophic lateral sclerosis or C9ORF72 amyotrophic lateral sclerosis. In one aspect, provided herein is a method of reducing neurodegeneration from traumatic brain injury, comprising administering to an individual in need thereof a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II- D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a Attorney Docket No.: 185992002240 pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, provided herein is a method of reducing neurodegeneration from traumatic brain injury, comprising administering to an individual in need thereof a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In one aspect, provided herein is a method of modulating TDP-43, comprising contacting a cell with an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, provided herein is a method of modulating TDP-43, comprising contacting a cell with an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, modulating TDP-43 comprises modulating TDP-43 incorporation into condensates, modulating TDP-43 binding to RNA in condensates, modulating TDP-43 aggregation, or modulating TDP43 protein-protein interactions. In some Attorney Docket No.: 185992002240 embodiments, modulating TDP-43 comprises modulating TDP-43 incorporation into condensates. In some embodiments, modulating TDP-43 comprises modulating TDP-43 binding to RNA in condensates. In some embodiments, modulating TDP-43 comprises modulating TDP-43 aggregation. In some embodiments, modulating TDP-43 comprises modulating TDP43 protein-protein interactions. In some embodiments, modulating TDP-43 comprises mitigating TDP-43 interaction to RNA condensates, mitigating TDP-43 aggregation, or mitigating TDP-43 protein-protein interactions. In some embodiments, modulating TDP-43 comprises mitigating TDP-43 interaction to RNA condensates. In some embodiments, modulating TDP-43 comprises mitigating TDP-43 aggregation. In some embodiments, modulating TDP-43 comprises mitigating TDP-43 protein-protein interactions. In one aspect, provided herein is a method of directly modulating TDP-43, comprising contacting a cell with an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, provided herein is a method of directly modulating TDP-43, comprising contacting a cell with an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the methods selectively modulate TDP-43. In some embodiments, the methods reduce TDP-43 cytoplasmic inclusions, improve nuclear TDP-43 function, or reduce neurodegeneration. In some embodiments, the methods reduce TDP-43 cytoplasmic inclusions. In some embodiments, the methods improve nuclear TDP-43 function. In some embodiments, the methods reduce neurodegeneration. In some embodiments, the methods mitigate TDP-43 cytoplasmic condensates in motor neurons. In some embodiments, the motor neurons are iPSC-derived Attorney Docket No.: 185992002240 motor neurons. In some embodiments, STMN2 and POLDIP3 splicing in iPSC-derived motor neurons is restored. In one aspect, provided herein is a method of modulating TDP-43 driven gene expression levels, comprising contacting a cell with an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, provided herein is a method of modulating TDP-43 driven gene expression levels, comprising contacting a cell with an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II- B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the gene expression levels are for STMN2 or POLDIP3. In some embodiments, the gene expression levels are for STMN2. In some embodiments, the gene expression levels are for POLDIP3. In some embodiments, the methods selectively modulate TDP-43. In some embodiments, the methods reduce TDP-43 cytoplasmic inclusions, improve nuclear TDP-43 function, or reduce neurodegeneration. In some embodiments, the methods reduce TDP-43 cytoplasmic inclusions. In some embodiments, the methods improve nuclear TDP-43 function. In some embodiments, the methods reduce neurodegeneration. In some embodiments, the methods mitigate TDP-43 cytoplasmic condensates in motor neurons. In some embodiments, the motor neurons are iPSC-derived motor neurons. In some embodiments, STMN2 and POLDIP3 splicing in iPSC-derived motor neurons is restored. In one aspect, provided herein is a compound of formula (I), or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically Attorney Docket No.: 185992002240 acceptable salt, hydrate, or solvate of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in the treatment of a disease or condition mediated by TDP-43. In some embodiments, provided herein is a compound of formula (I), or any variation or embodiment thereof, such as (II), (II- A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in the treatment of a disease or condition mediated by TDP-43. In one aspect, provided herein is the use of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients, in the manufacture a medicament for the treatment of a disease or condition mediated by TDP-43. In some embodiments, provided herein is the use of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, in the manufacture a medicament for the treatment of a disease or condition mediated by TDP-43. Attorney Docket No.: 185992002240 KITS The present disclosure further provides kits for carrying out the methods disclosed herein. The kits may comprise a compound, or stereoisomer or tautomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof as described herein and suitable packaging. The kits may comprise one or more containers comprising any compound described herein. In one aspect, a kit includes a compound of the disclosure or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a label and/or instructions for use of the compound in the treatment of a disease or disorder described herein. The kits may comprise a unit dosage form of the compound. In some embodiments, the kits may comprise a compound, or stereoisomer or tautomer thereof, or pharmaceutically acceptable salt thereof. Provided herein are kits, comprising (i) an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and (ii) instructions for use in treating a TDP-43 mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, the kits comprise (i) a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating a TDP-43 mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, the kits comprise (i) an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating a TDP-43 mediated disease, disorder, or condition in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in treating a TDP-43 mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, the kits comprise (i) a Attorney Docket No.: 185992002240 pharmaceutical composition comprising an effective amount of a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II- D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in treating a TDP-43 mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, the individual is a human. Articles of manufacture are also provided, wherein the article of manufacture comprises a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, in a suitable container. In some embodiments, the article of manufacture comprises a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. Also provided herein are articles of manufacture, comprising a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, in a suitable container. In some embodiments, the articles of manufacture comprise a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, such as (II), (II-A), (II-B), (II-C), (II-D), (II-D-1), (II-D-2), (III), (III-A), (III-B), (IV), or (IV- A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag. METHODS OF PREPARING The present disclosure further provides processes for preparing the compounds of present invention. In some aspects, provided herein are processes of preparing a compound of formula (I), or any variation or embodiment thereof or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In some embodiments, provided herein are processes of preparing a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically Attorney Docket No.: 185992002240 acceptable salt of any of the foregoing. In some embodiments, provided herein are processes of preparing a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof. The following synthetic reaction schemes, which are detailed in the Schemes and Examples, are merely illustrative of some of the methods by which the compounds of the present disclosure, or an embodiment or aspect thereof, can be synthesized. Various modifications to these synthetic reaction schemes can be made, as will be apparent to those of ordinary skill in the art. As depicted in the Schemes and Examples below, in certain exemplary embodiments, compounds of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, are prepared according to the general procedures. The general methods below, and other methods known to synthetic chemists of ordinary skill in the art, can be applied to all formulae, embodiments, and species described herein. The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data. Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure, or any variation or embodiment thereof, may be prepared using appropriate starting materials according to the methods described generally herein and/or by methods available to one of ordinary skill in the art. All the products generated from the following reactions can be isolated and purified employing standard techniques, such as extraction, prep-TLC, ion exchange chromatography, chromatography on silica gel, prep-HPLC. Specific purification steps and methods were set up and will be referred to in the text as follows. Compounds may be prepared by methods known in the art of organic chemistry as set forth in part by the following synthesis schemes. In all the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P.G.M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley et Sons, hereby incorporated by reference in its entirety). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. Attorney Docket No.: 185992002240 The compound may be represented as a mixture of enantiomers, which may be resolved into the individual pure R- or S-enantiomers. Commercial nitrobenzene and aniline were used as starting material A.1 (Schemes 1, 2, 3 and 4) for the synthesis of 6,7-disubstituted 2,4-dichloroquinoline A.4. Commercial materials were used as such for cyclization step (step 3) to form the quinolines A.4 or underwent two former steps: a first step to further substitute compound A.1 in position 3 by reductive amination, aromatic nucleophilic substitution, or methylation to get A.2, and a second step for the reduction of nitro-groups or deacylation of methylamide to get the free aniline A.3. The derivative 2,4-dichloroquinoline A.4 was then formed by cyclization of A.3 with malonic acid in phosphoryl chloride. The 2,4-dichloroquinoline A.4 underwent a Suzuki cross coupling with commercially available or synthesized boronic ester reagents (Scheme 1). Quinolines A.4 were selectively substituted in position 2 to give compounds A.5. The substitution of position 4 of compound A.5 was realized by Buchwald cross coupling or by aromatic nucleophilic substitution with commercial or synthesized amines and allowed the formation of FP (Final Product). SCHEME 1.
Figure imgf000203_0001
Similarly to Scheme 1, other FP were synthesized applying first the Buchwald coupling or the nucleophilic aromatic substitution of position 4 of quinolines A.4 to give derivatives B.1 (Scheme 2). This step was then followed by a Suzuki coupling to give FP. Attorney Docket No.: 185992002240 SCHEME 2.
Figure imgf000204_0001
In some cases, the substituted (hetero)aromatic ring added during the Suzuki coupling on quinolines A.4 contains a PG (Protecting Group, Schemes 3 and 4). In these cases, FP were obtained after an additional step of deprotection. Scheme 3 describes the synthetic sequence similar to Scheme 1, with a Suzuki cross coupling realized first on quinolines A.4, followed by the substitution of quinolines C.1 using a Buchwald reaction or a nucleophilic aromatic substitution to give compounds C2. Compound C.2 underwent then a deprotection step to give FP. SCHEME 3.
Figure imgf000204_0002
Scheme 4 describes a synthetic sequence similar to Scheme 2, where derivative B.1 is obtained after a Buchwald or aromatic nucleophilic substitution realized on quinolines A.4 and followed by a Suzuki cross coupling, and coupling FP are obtained by deprotection of compounds C.2. SCHEME 4.
Figure imgf000204_0003
Attorney Docket No.: 185992002240 Scheme 5 describes a synthetic sequence where A.5 was obtained following Scheme 1 and where the Buchwald coupling reaction is done with an opened or cyclized amine linked to a PG. to get D.1 intermediates. FP is obtained after an additional step of deprotection. SCHEME 5.
Figure imgf000205_0001
Scheme 6 describes a synthetic sequence where an opened or cyclized amine used for the Buchwald coupling or aromatic substitution on C.1, obtained from Scheme 3, held a protecting group PG’ to get compound E.1. Compound E.1 is then fully deprotected to give FP. SCHEME 6.
Figure imgf000205_0002
Enumerated Embodiments Enumerated Embodiment 1. A compound of formula (I):
Figure imgf000205_0003
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein: R1 and R2 are each independently C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl wherein Attorney Docket No.: 185992002240 the C1-6alkyl of R1 or R2 is optionally substituted with one or more R1a, the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1 or R2 is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), -S(=O)2R14, -S(=O)2N(R13)(R14), or C3-8cycloalkyl group of R1 or R2 are taken together with the atoms to which they are attached to form a C3- 8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1b; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl of R1 and R2 is optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R3 is optionally substituted with one or more R3a, and optionally, two substituents of R3 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl is optionally substituted one or more R3b; Ring A is 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein Attorney Docket No.: 185992002240 the 4- to 12-membered cycloalkenyl, 4- to 12-membered unsaturated heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 12-membered unsaturated heterocyclyl or 5- to 10-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R4 is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4 is optionally substituted with one or more R4b, and the 3- to 8-membered heterocyclyl of R4 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-, wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)- is optionally substituted by one or more RL; each RL is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RL are taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R5 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R14, -S(=O)2R14, -S(=O)2N(R13)(R14), or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, - S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, or -S(=O)2N(R13)(R14), and Attorney Docket No.: 185992002240 the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -SR12, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, - OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, - C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, - S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, - S(=NR15)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R6 is optionally substituted by one or more R6a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R6 is optionally substituted with one or more R6b, - C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14, and the 3- to 8-membered heterocyclyl of R6 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R6 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R6b; R7, R8, R9, and R10 are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - OR11, -OR12, -SR12, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, - N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, - S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, -S(=NR15)OR14, -S(=O)2R14, - S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R7, R8, R9, or R10 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R7, R8, R9, or R10 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R7, R8, R9, or R10 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and Attorney Docket No.: 185992002240 optionally, two substituents of R7, R8, R9, or R10 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R7b; each R1a, R3a, R4a, R6a, or R7a is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, - CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, - OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, - C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, - S(=O)R14, -S(=O)2R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=NR15)R14, -S(=NR15)N(R13)R14, - S(=NR15)OR14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R3a, R4a, R6a, or R7a is optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R3a, R4a, R6a, or R7a comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, -N(Rx)(Ry), oxo, - CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; each R11 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R11 is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry), and the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R11 is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 12-membered heterocyclyl; each R12 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, Attorney Docket No.: 185992002240 wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, C1- 6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R13 is independently H, C1-6alkyl, or C3-8cycloalkyl; each R14 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, - N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl is optionally substituted by -OH, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, -OH, or -N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl). Enumerated Embodiment 2. The compound of Enumerated Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein: R1 and R2 are each independently C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), or C3-8cycloalkyl, wherein the C1-6alkyl of R1 or R2 is optionally substituted with one or more R1a, the C3-8cycloalkyl of R1 or R2 is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R14, -C(=O)OR14, - C(=O)N(R13)(R14), or C3-8cycloalkyl group of R 1 or R2 are taken together with the atoms to which they are attached to form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1b; Attorney Docket No.: 185992002240 or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; Ring A is 4- to 8-membered monocyclic cycloalkenyl, 4- to 8-membered unsaturated monocyclic heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 8-membered monocyclic cycloalkenyl, 4- to 8-membered unsaturated monocyclic heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 8-membered unsaturated monocyclic heterocyclyl or 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; and R6 is -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R13)(R14), -C(=NR15)N(R13)R14, - N(R13)S(=O)2R14, -S(=O)N(R13)R14, -S(=O)2N(R13)(R14), or 3- to 12-membered N-containing heterocyclyl, wherein the 3- to 12-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14, and the 3- to 12-membered N-containing heterocyclyl of R6 further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; wherein (i) when Ring A is phenyl and R6 is selected from the group consisting of -NH2, - NHCH3, and -N(CH3)3, R1 and R2 are not both C1-2alkyl; (ii) when R1 and R2 are taken together with the N to which they are attached to form a 4-methylpiperazinyl, -(Ring A)-X-L-R6 is not
Figure imgf000211_0001
(iii) when R1 and R2 are taken together with the N to which they are attached to form a morpholinyl, R6 is not selected from the group consisting of -NH2, -NHC(O)CH3, and - NHC(O)O-C(CH3)3; and (iv) when Ring A is pyridin-4yl substituted with -NHC(CH3)phenyl, R1 and R2 are not taken together with the N to which they are attached to form an optionally substituted 2,5- diazabicyclo[2.2.2]octanyl. Attorney Docket No.: 185992002240 Enumerated Embodiment 3. The compound of Enumerated Embodiment 1 or 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein: R1 and R2 are each independently C1-6alkyl, C2-6alkenyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R1 or R2 is optionally substituted with one or more R1a, the C3-8cycloalkyl of R1 or R2 is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, or C3-8cycloalkyl group of R1 or R2 are taken together with the atoms to which they are attached to form a C3- 8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1b; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R 13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R 14, - S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R3 is optionally substituted with one or more R3a, and optionally, two substituents of R3 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10- membered aryl, or 5- to 10-membered heteroaryl is optionally substituted one or more R3b; each R4 is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -SR12, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R14, - Attorney Docket No.: 185992002240 S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R4 is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4 is optionally substituted with one or more R4b, and the 3- to 8-membered heterocyclyl of R4 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; R5 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)R14, -OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), - C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, - N(R13)S(=O)2R14, -S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R14, or - S(=O)2N(R13)(R14), and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R13)(R14), -C(=NR15)N(R13)R14, - N(R13)S(=O)2R14, -S(=O)N(R13)R14, -S(=O)2N(R13)(R14), or 3- to 12-membered N-containing heterocyclyl, wherein the 3- to 12-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14, and the 3- to 12-membered N-containing heterocyclyl of R6 further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; R7, R8, R9, and R10 are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - OR11, -OR12, -SR12, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R13)C(=O)R14, - N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, -OC(=O)N(R13)R14, - OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, -C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, -S(=O)R14, -S(=O)2R14, - S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R7, R8, R9, or R10 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R7, R8, R9, or R10 is optionally substituted with one or more R7b, and Attorney Docket No.: 185992002240 the 3- to 8-membered heterocyclyl of R7, R8, R9, or R10 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R7, R8, R9, or R10 are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R7b; each R1a, R3a, R4a, R6a, or R7a is independently halo, -N(Rx)(Ry), -OR12, -SR12, -SF5, -NO2, - CN, -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, -OC(=O)R14, - OC(=O)N(R13)R14, -OC(=O)OR14, -C(=O)R14, -C(=O)N(R13)(R14), -C(=O)OR14, - C(=NR15)R14, -C(=NOR14)R14, -C(=NR15)N(R13)R14, -C(=NR15)OR14, -N(R13)S(=O)2R14, - S(=O)R14, -S(=O)N(R13)R14, -S(=O)OR14, -S(=O)2R14, -S(=O)2N(R13)(R14), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R3a, R4a, R6a, or R7a is optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R3a, R4a, R6a, or R7a comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, -N(Rx)(Ry), oxo, - CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R11 is independently H, C1-6alkyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C1-6alkyl of R11 is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry), and the phenyl or 5- to 6-membered heteroaryl of R11 is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R12 is independently H, C1-6alkyl, or C3-8cycloalkyl, Attorney Docket No.: 185992002240 wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, C1- 6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R13 is independently H, C1-6alkyl, or C3-8cycloalkyl; each R14 is independently H, C1-6alkyl, C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -N(Rx)(Ry), C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12- membered heterocyclyl, and the C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, or -N(Rx)(Ry); and each R15 is independently H or C1-6alkyl. Enumerated Embodiment 4. The compound of any of Enumerated Embodiments 1-3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein: R1 and R2 are each independently C1-6alkyl optionally substituted with one or more R1a; or R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, oxo, -OR 12, or -N(Rx)(Ry) wherein the C1-6alkyl of R3 is optionally substituted with R3a; R4 is halo, C1-6alkyl, or -OR 12; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-; R5 is H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), or - OR12, and the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, -N(R13)C(=O)OR14, - OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R13)(R14), -N(R13)S(=O)2R14, - S(=O)N(R13)R14, -S(=O)2N(R13)(R14), or 3- to 12-membered N-containing heterocyclyl, wherein the 3- to 12-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or -C(=O)OR14, and the 3- to 12-membered N-containing heterocyclyl of R6 further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; R7 is H; Attorney Docket No.: 185992002240 R8 and R9 are each independently H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(O)R14, - N(R13)C(O)OR14, -N(R13)C(O)N(R13)R14, -OC(O)R14, -OC(O)OR14, -OC(O)N(R13)R14, - C(O)R14, -C(O)OR14, or -C(O)N(R13)(R14) , wherein the C1-6alkyl of R8 or R9 is optionally substituted by one or more R7a; R10 is H; each R1a, R3a, R4a, R6a, or R7a is independently -OR12 or -N(Rx)(Ry); each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR 11, or -N(Rx)(Ry), wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R11 is independently H or C1-6alkyl; each R12 is independently H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, or - N(Rx)(Ry); and each R13 is independently H or C1-6alkyl. Enumerated Embodiment 5. The compound of any of Enumerated Embodiments 1-4, wherein the compound is a compound of formula (II):
Figure imgf000216_0001
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein X1 is N or CH, and n is 0, 1, 2, 3, or 4. Attorney Docket No.: 185992002240 Enumerated Embodiment 6. The compound of Enumerated Embodiment 5, wherein the compound is a compound of formula (II-A):
Figure imgf000217_0001
pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. Enumerated Embodiment 7. The compound of Enumerated Embodiment 5, wherein the compound is a compound of formula (II-B):
Figure imgf000217_0002
pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. Enumerated Embodiment 8. The compound of Enumerated Embodiment 5, wherein the compound is a compound of formula (II-C):
Figure imgf000217_0003
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. Attorney Docket No.: 185992002240 Enumerated Embodiment 9. The compound of any of Enumerated Embodiments 1-4, wherein the compound is a compound of formula (III):
Figure imgf000218_0001
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein X1 is N or CH; and n is 0, 1, 2, 3, or 4. Enumerated Embodiment 10. The compound of Enumerated Embodiment 9, wherein the compound is a compound of formula (III-B):
Figure imgf000218_0002
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. Enumerated Embodiment 11. The compound of any of Enumerated Embodiments 1- 10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein: R1 and R2 are taken together with the N to which they are attached to form a 3- to 12- membered heterocyclyl optionally substituted with one or more R3; R8 is H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(O)R14, -N(R13)C(O)OR14, - N(R13)C(O)N(R13)R14, -C(O)N(R13)(R14), or C3-6cycloalkyl, wherein the C1-6alkyl of R8 is optionally substituted by one or more R7a; and R9 is H, halo, C1-6alkyl, -OR12, -CN, or C3-6cycloalkyl, wherein the C1-6alkyl of R9 is optionally substituted by one or more R7a. Attorney Docket No.: 185992002240 Enumerated Embodiment 12. The compound of any of Enumerated Embodiments 1-4, wherein the compound is a compound of formula (III):
Figure imgf000219_0001
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein X2, X4 and X5 are each independently C, N, O or S; X3 and X6 are each independently C or N; and n is 0, 1, 2, or 3. Enumerated Embodiment 13. The compound of Enumerated Embodiment 10, wherein the compound is a compound of formula (III-A):
Figure imgf000219_0002
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. Enumerated Embodiment 14. The compound of any of Enumerated Embodiments 1-4, wherein Ring A is phenyl or 5- to 6-membered heteroaryl. Enumerated Embodiment 15. The compound of Enumerated Embodiment 14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein Ring A is selected from the group consisting of phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furan, thiophene, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, and triazinyl. Enumerated Embodiment 16. The compound of Enumerated Embodiment 15, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein Ring A is phenyl, thiazolyl, or pyridinyl. Enumerated Embodiment 17. The compound of any of Enumerated Embodiments 1- 10, or 12-16, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, Attorney Docket No.: 185992002240 hydrate, or solvate of any of the foregoing, wherein R1 and R2 are each independently C1- 6alkyl optionally substituted with one or more R1a. Enumerated Embodiment 18. The compound of Enumerated Embodiment 17, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R1 and R2 are each independently C1-4alkyl optionally substituted with one or more R1a. Enumerated Embodiment 19. The compound of Enumerated Embodiment 17 or 18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein each R1a is independently -OH, -NH2, -NH(C1-6alkyl), - N(C1-6alkyl)(C1-6alkyl), -NH(C3-6cycloalkyl), or -N(C1-6alkyl)(C3-6cycloalkyl). Enumerated Embodiment 20. The compound of any of Enumerated Embodiments 17- 19, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein each R1a is independently -OH, -NH2, -NH(C1- 4alkyl), -N(C1-4alkyl)(C1-4alkyl), -NH(C3-6cycloalkyl), or -N(C1-4alkyl)(C3-6cycloalkyl). Enumerated Embodiment 21. The compound of any of Enumerated Embodiments 17- 20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein each R1a is independently -OH, -NH2, -NH(CH3), - N(CH3)(CH3), -NH(CH2CH3), -N(CH3)(CH2CH3), or -N(CH2CH3)(CH2CH3). Enumerated Embodiment 22. The compound of any of Enumerated Embodiments 1- 16, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R1 and R2 are taken together with the N to which they are attached to form a 3- to 12-membered heterocyclyl optionally substituted with one or more R3, wherein the 3- to 12-membered heterocyclyl comprises a 3- to 8-membered monocyclic heterocyclyl, a 5- to 12-membered fused heterocyclyl, or a 6- to 12-membered spirocyclic heterocyclyl. Enumerated Embodiment 23. The compound of any of Enumerated Embodiments 1- 16, or 22, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R1 and R2 are taken together with the N to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with one or more R3. Enumerated Embodiment 24. The compound of Enumerated Embodiment 22 or 23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein the R1 and R2 are taken together with the N to which they Attorney Docket No.: 185992002240 are attached to form a 4- to 7-membered monocyclic heterocyclyl optionally substituted with one or more R3. Enumerated Embodiment 25. The compound of any of Enumerated Embodiments 22- 24, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein the R1 and R2 are taken together with the N to which they are attached to form a pyrrolidinyl or diazepanyl optionally substituted with one or more R3. Enumerated Embodiment 26. The compound of any of Enumerated Embodiments 22- 25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein each R3 is independently -OH, C1-6alkyl, C1-6alkoxy, or -N(Rx)(Ry) wherein the C1-6alkyl of the R3 is optionally substituted with R3a. Enumerated Embodiment 27. The compound of Enumerated Embodiment 26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein each R3 is independently -OH, C1-4alkyl, C1-4alkoxy, -NH2, - NH(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -NH(C3-6cycloalkyl), or -N(C1-4alkyl)(C3- 6cycloalkyl), wherein the C1-4alkyl of the R3 is optionally substituted with R3a. Enumerated Embodiment 28. The compound of Enumerated Embodiment 27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein each R3 is independently -OH, -CH3, -CH2OH, -OCH3, or - NH2. Enumerated Embodiment 29. The compound of any of Enumerated Embodiments 22- 25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein the R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group consisting
Figure imgf000221_0001
Figure imgf000221_0002
Enumerated Embodiment 30. The compound of Enumerated Embodiment 22 or 23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein the R1 and R2 are taken together with the N to which they Attorney Docket No.: 185992002240 are attached to form a 6- to 12-membered fused heterocyclyl optionally substituted with one or more R3. Enumerated Embodiment 31. The compound of Enumerated Embodiment 30, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein each R3 is independently C1-6alkyl or oxo. Enumerated Embodiment 32. The compound of Enumerated Embodiment 31, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein each R3 is independently -CH3 or oxo. Enumerated Embodiment 33. The compound of any of Enumerated Embodiments 22, 23 or 30, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein the R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group consisting of
Figure imgf000222_0001
Enumerated Embodiment 34. The compound of Enumerated Embodiment 22 or 23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein the R1 and R2 are taken together with the N to which they are attached to form a 6- to 12-membered spirocyclic heterocyclyl optionally substituted with one or more R3. Enumerated Embodiment 35. The compound of Enumerated Embodiment 34, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein each R3 is halo. Enumerated Embodiment 36. The compound of Enumerated Embodiment 35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein each R3 is F. Enumerated Embodiment 37. The compound of any of Enumerated Embodiments 22, 23 or 34, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein the R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group consisting of Attorney Docket No.: 185992002240
Figure imgf000223_0001
. Enumerated Embodiment 38. The compound of any of Enumerated Embodiments 1-5, 12, or 14-37, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R4 is halo or -O-(C1-6alkyl). Enumerated Embodiment 39. The compound of any of Enumerated Embodiments 1-5, 12, or 14-38, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R4 is halo or -OCH3. Enumerated Embodiment 40. The compound of any of Enumerated Embodiments 1- 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R5 is H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), -OR12, and the C3-8cycloalkyl of R5 is optionally substituted with one or more R5b. Enumerated Embodiment 41. The compound of any of Enumerated Embodiments 1- 40, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R5 is H, C1-6alkyl, or C3-8cycloalkyl. Attorney Docket No.: 185992002240 Enumerated Embodiment 42. The compound of any of Enumerated Embodiments 1- 41, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R5 is H or C1-6alkyl. Enumerated Embodiment 43. The compound of any of Enumerated Embodiments 1- 42, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R5 is H. Enumerated Embodiment 44. The compound of any of Enumerated Embodiments 1- 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein L is a bond or -O-(C1-6alkyl)-. Enumerated Embodiment 45. The compound of any of Enumerated Embodiments 1- 39, or 44, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein L is a bond or -O-(CH2CH2)-. Enumerated Embodiment 46. The compound of any of Enumerated Embodiments 1- 45, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R6 is -N(Rx)(Ry). Enumerated Embodiment 47. The compound of Enumerated Embodiment 1-46, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R6 is selected from the group consisting of
Figure imgf000224_0001
,
Figure imgf000224_0002
Enumerated Embodiment 48. The compound of any of Enumerated Embodiments 1- 45, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R6 is -N(R13)C(O)R14, -N(R13)C(O)OR14, - N(R13)C(O)N(R13)R14, -C(O)N(R13)(R14), -C(O)(C1-6alkyl)N(R13)(R14). Enumerated Embodiment 49. The compound of any of Enumerated Embodiments 1- 45 or 48, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R6 is -N(R13)C(O)R14 or -C(O)(C1- 6alkyl)N(R13)(R14). Enumerated Embodiment 50. The compound of any of Enumerated Embodiments 1- 45, 46, or 49, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, Attorney Docket No.: 185992002240 hydrate, or solvate of any of the foregoing, wherein
Figure imgf000225_0001
Figure imgf000225_0002
. Enumerated Embodiment 51. The compound of any of Enumerated Embodiments 1- 45, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R6 is 3- to 12-membered N-containing heterocyclyl optionally substituted with one or more R6b. Enumerated Embodiment 52. The compound of any of Enumerated Embodiments 1- 45 or 50, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein L is a bond and R6 is 3- to 12-membered N-containing heterocyclyl optionally substituted with one or more R6b. Enumerated Embodiment 53. The compound of any of Enumerated Embodiments 1- 44, 50, or 52, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R6 is azetidinyl, pyrrolidinyl, or piperazinyl, wherein the azetidinyl, pyrrolidinyl, or piperazinyl is optionally substituted with one or more R6b. Enumerated Embodiment 54. The compound of Enumerated Embodiment 1-45 or 51- 53, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R6 is selected from the group consisting of
Figure imgf000225_0003
Attorney Docket No.: 185992002240
Figure imgf000226_0001
Enumerated Embodiment 55. The compound of any of Enumerated Embodiments 1- 10, or 12-54, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R8 and R9 are each independently H, halo, -N(Rx)(Ry), -OR11, -N(R13)C(O)R14, or -N(R13)C(O)OR14. Enumerated Embodiment 56. The compound of Enumerated Embodiment 55, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R8 and R9 are each independently H, halo, -NH2, -N(C1- 6alkyl)(C1-6alkyl), -O(C1-6alkyl), -NHC(O)(5- to 6-membered aryl), or -NHC(O)O(C1-6alkyl), wherein the 5- to 6-membered aryl of -NHC(O)(5- to 6-membered aryl) is optionally substituted with -N(C1-6alkyl)(C1-6alkyl). Enumerated Embodiment 57. The compound of Enumerated Embodiment 56, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R8 and R9 are each independently H, F, Cl, -NH2, - N(CH3)(CH3), -OCH3, -NHC(O)(phenyl), or -NHC(O)O(CH2CH3), wherein the phenyl of -NHC(O)(phenyl) is substituted with -N(CH3)(CH3). Enumerated Embodiment 58. The compound of any of Enumerated Embodiments 1- 57, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R8 and R9 are each H. Enumerated Embodiment 59. The compound of any of Enumerated Embodiments 1-4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein: R1 and R2 are taken together with the N to which they are attached to form a 4- to 12- membered heterocyclyl optionally substituted with one or more R3; Ring A is pyridinyl; and L is a bond or -O-(C1-6alkyl)-. Attorney Docket No.: 185992002240 Enumerated Embodiment 60. The compound of Enumerated Embodiment 59, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein: R1 and R2 are taken together with the N to which they are attached to form a 4- to 12- membered heterocyclyl optionally substituted with one or more R3; Ring A is pyridinyl; L is a bond; and R6 is piperazinyl optionally substituted with one or more R6b. Enumerated Embodiment 61. The compound of any of Enumerated Embodiments 1-4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein: R1 and R2 are taken together with the N to which they are attached to form a 4- to 12- membered heterocyclyl optionally substituted with one or more R3; and R8 and R9 are each independently H, F, -N(CH3)(CH3), -OCH3 or -OCD3. Enumerated Embodiment 62. The compound of Enumerated Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein the compound is selected from Table 1. Enumerated Embodiment 63. A pharmaceutical composition comprising a compound of any of Enumerated Embodiments 1-62, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients or carriers. Enumerated Embodiment 64. A method for treating a disease or condition mediated by TDP-43, comprising administering to a subject in need thereof a compound of any of Enumerated Embodiments 1-62, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or the pharmaceutical composition of Enumerated Embodiment 63. Enumerated Embodiment 65. The method of Enumerated Embodiment 64, wherein a therapeutically effective amount of the compound is administered. Enumerated Embodiment 66. The method of Enumerated Embodiment 64 or 65, wherein said disease or condition mediated by TDP-43 is a neurological disease or condition. Enumerated Embodiment 67. The method of Enumerated Embodiment 66, wherein the neurological disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), inclusion body myositis, Perry Attorney Docket No.: 185992002240 syndrome, corticobasaldegeneration, spinocerebellar ataxia type 3, and amyotrophic lateral sclerosis (ALS). Enumerated Embodiment 68. The method of Enumerated Embodiment 66 or 67, wherein the neurological disease or condition is traumatic brain injury (TBI). Enumerated Embodiment 69. The method of Enumerated Embodiment 66 or 67, wherein the neurological disease or condition is frontotemporal dementia (FTD). Enumerated Embodiment 70. The method of Enumerated Embodiment 66 or 67, wherein the neurological disease or condition is amyotrophic lateral sclerosis (ALS). Enumerated Embodiment 71. The method of any of Enumerated Embodiments 66, 67, or 70, wherein the neurological disease or condition is sporadic amyotrophic lateral sclerosis or C9ORF72 amyotrophic lateral sclerosis. Enumerated Embodiment 72. The method of any of Enumerated Embodiments 64-71, wherein the subject is a human. Enumerated Embodiment 73. A method of modulating TDP-43, comprising contacting a cell with an effective amount of a compound of any of Enumerated Embodiments 1-62, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or the pharmaceutical composition of Enumerated Embodiment 63, wherein modulating TDP-43 comprises modulating TDP-43 incorporation into condensates, modulating TDP-43 binding to RNA in condensates, modulating TDP-43 aggregation, or modulating TDP43 protein-protein interactions. Enumerated Embodiment 74. A method of modulating TDP-43 driven gene expression levels, comprising contacting a cell with an effective amount of a compound of any of Enumerated Embodiments 1-62, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or the pharmaceutical composition of Enumerated Embodiment 63. Enumerated Embodiment 75. The method of Enumerated Embodiment 74, wherein the gene expression levels are for STMN2. Enumerated Embodiment 76. The method of Enumerated Embodiment 74, wherein the gene expression levels are for POLDIP3. Enumerated Embodiment 77. The compound of any of Enumerated Embodiments 1- 62, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or the pharmaceutical composition of Enumerated Embodiment 63 for use in the treatment of a disease or condition mediated by TDP-43. Attorney Docket No.: 185992002240 Enumerated Embodiment 78. Use of a compound of any of Enumerated Embodiments 1-62, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof in the manufacture of a medicament for the treatment of a disease or condition mediated by TDP-43. Enumerated Embodiment 79. A kit, comprising (i) a compound of any one of Enumerated Embodiments 1-62, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or the pharmaceutical composition of Enumerated Embodiment 63 and (ii) instructions for use in treating a TDP-43 mediated disease or condition in an individual in need thereof. EXAMPLES The reagents and starting materials are commercially available and/or, using well- known techniques, can be readily synthesized by one of ordinary skill in the art. Unless otherwise noted, all commercially starting materials were used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification. Table 2.
Figure imgf000229_0001
Attorney Docket No.: 185992002240
Figure imgf000230_0001
SCX general protocol. The hydrochloride salt product was neutralized by Strong Cation Exchange Resin. The resin was first washed with two volumes of deionized water. The compound to neutralized was absorbed to the resin by washing the resin with a solution Attorney Docket No.: 185992002240 of the compound in methanol. The resin was then washed with deionized water until the pH of the solution is neutral. A solution of ammonium hydroxide and methanol was used to release compound from the resin. Solvents were then concentrated and lyophilized to get the desired product. Prep-HPLC. Experiments were carried out at room temperature and detection was done by UV at 220 and 254 nm. The different methods used are described as follows. 1: ACSWH-GX-N; YMC triart C18 column 150 x 25 mm x 5 mm; mobile phase: water (HCl)- ACN 2: ACSWH-GX-N; Phenomenex Luna C18 column 150 x 25 mm x 10 mm; mobile phase: water (FA)-ACN 3: ACSWH-GX-N; Phenomenex Luna C18 column 150 x 25 mm x 10 mm; mobile phase: water (TFA)-ACN 4: ACSWH-GX-N; Unisil 3-100 C18 ultra column 150 x 50 mm x 3 mm; mobile phase: water (0.23% FA)-ACN 5: Agilent Infinity II 1260/1290, Agilent Infinity Lab Poroshell 1204; HPH-C18 column 21.2 x 150 mm; mobile phase: water (0.1% FA)-ACN (0.1% FA) 6 (basic system): Agilent Infinity II 1260/1290, Agilent Infinity Lab Poroshell 1204; HPH- C18 column 21.2 x 150 mm; mobile phase: water-ACN (0.1 % NH3) 7: ACSWH-GX-N; Waters Xbridge 150 x 25 mm x 5 mm; mobile phase: water (ammonia hydroxide v/v)-ACN 8: ACSWH-GX-O; Phenomenex luna C18150 x 25 mm x 10 mm; mobile phase: water (HCl)- ACN 9: ACSWH-GX-A; YMC Triart C18 150 x 25 mm x 5 mm); mobile phase: water (ammonia hydroxide v/v)-ACN 10: ACSWH-GX-N; Welch Xtimate C18150 x25mm x 5um; mobile phase: water (FA)-ACN 11: ACSWH-GX-N; Waters Xbridge 150 x 25 mm x 5 mm; mobile phase: water (water (FA)- ACN Flash silica gel chromatography. ISCO®; SepaFlash® Silica Flash Column, Eluent Ethyl acetate/Petroleum ether gradient Flash chromatography. Puri Flash XS520Plus, Interchim, PF-30SIHP-JP-F00xx, 30 μm NMR and LCMS. The analytical characterization of synthesized compounds was done by NMR and LCMS. 1H NMR spectra were recorded on a Bruker AVANCE III 400, Bruker AVANCE NEO 400, Bruker AVANCE III HD 400 or on a Jeol ECZ 400 Attorney Docket No.: 185992002240 spectrometer at 400 MHz Data are reported as follows: chemical shift in ppm, deuterated solvent (CDCl3 for deuterated chloroform, DMSO-d6 for deuterated dimethylsulfoxide and methanol-d4 for deuterated methanol), multiplicity (s = singulet, d = doublet, t = triplet, q = quartet, m = multiplet or overlap of non-equivalent resonances, integration, br = broad singulet, dd = doublet of doublet, dt = doublet of triplet, td = triplet of doublet, dq = doublet of quintuplet). Coupling constants J were measured in Hertz. LCMS spectra were recorded according to the following conditions: - SHIMADZU LCMS-2020 using LabSolution software Version 5.89 and 5.93; HALO C18 column 3.0 x 30 mm x 5.0 um or Kinetex EVO C18 column 2.1 x 30 mm x 5 um; mobile phase: water (0.04% TFA)-ACN (0.02% TFA), at 50 °C on a 1 to 2 minutes gradient (flow rate 1.5 to 2.0 mL/min) with UV detection at 220 and 254 nm; ESI for mass spectra. - Agilent 1260 Infinity II, Agilent Poroshell 120 EC C18 or HPH C18 column 2.7 μm 2.1 x 50 mm; mobile phase: water (0.1% FA)-ACN on a two-minute gradient (flow rate 0.6 mL/min) or mobile phase: water (0.1% FA)-ACN on a five-minute gradient (flow rate 0.6 mL/min) or water (0.1% NH3)-ACN (flow rate 0.7 mL/min) with UV detection at 220 and 254 nm; ESI for mass spectra. Synthesis of non-commercially available boronic acids and esters bor.1’: [6-(1-tert-butoxycarbonylazetidin-3-yl)-3-pyridyl] boronic acid
Figure imgf000232_0002
Figure imgf000232_0001
Step 1: To a solution of 2,5-dibromopyridine 7.1 (3.0 g, 13 mmol, 1.0 eq) and tert- butyl 3-iodoazetidine-1-carboxylate (4.7 g, 16.5 mmol, 1.3 eq) in DME (30 mL) were added [4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate (0.14 g, 0.13 mmol, 0.01 eq), [4,4′- Bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride (25 mg, 0.06 mmol, 0.005 eq), bis(trimethylsilyl)silyl-trimethyl-silane (3.15 g, 13 mmol, 1.0 eq) and Na2CO3 (2.7 g, 25 mmol, 2.0 eq) at 25 °C. After stirring at 25 °C for 16 h under irradiation with a 455 nm blue LED, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The remaining mixture was purified by Flash chromatography (20 g column, Eluent Attorney Docket No.: 185992002240 of 0~60% EtOAc/PE gradient at 40 mL/min) to give tert-butyl 3-(5-bromo-2-pyridyl) azetidine-1-carboxylate 7.2 (1.0 g, 2.75 mmol, 22% yield, 86% purity) as yellow oil. MS m/z (ESI) [M-55] + = 259.0. Step 2: To a solution of tert-butyl 3-(5-bromo-2-pyridyl)azetidine-1-carboxylate 7.2 (1.0 g, 2.75 mmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,3,2-dioxaborolane (0.91 g, 3.6 mmol, 1.3 eq) in dioxane (25 mL) was added 1,1- bis(diphenylphosphino) ferrocene palladium(II) dichloride (0.20 g, 0.28 mmol, 0.10 eq) and potassium acetate (1.1 g, 11 mmol, 4.0 eq) at 20 °C. After stirring at 80 °C for 24 h, the reaction mixture was diluted with water (30 mL) and then extracted with ethyl acetate (30 mL, three times), the combined organic phase was washed with brine (10 mL, three times), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (12 g column, Eluent of 0~50% EtOAc/PE gradient at 40 mL/min) to give bor.1’ (0.45 g, 1.5 mmol, 54% yield, 91% purity) as a yellow gum. MS m/z (ESI) [M-80]+ = 223.3. bor.2: 2-(azetidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiazole
Figure imgf000233_0001
Step 1: To a solution of 2,5-dibromothiazole 8.1 (1.0 g, 4.1 mmol, 1.0 eq) in N, N- dimethylformamide (10 mL) was added potassium carbonate (1.1 g, 8.2 mmol, 2.0 eq) and azetidine (0.60 g, 6.4 mmol, 0.71 mL, 1.6 eq, HCl salt) at 25 °C. After stirring at 80 °C for 16 h, the reaction mixture was added into water (50 mL) and extracted with ethyl acetate 60 mL (20 mL, three times). The combined organic layers were washed with brine 60 mL (20 mL, three times), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (24g column, Eluent of 0~15% EtOAc/PE gradient at 45 mL/min) to give 2-(azetidin-1-yl)-5-bromo-thiazole 8.2 (0.50 g, 2.3 mmol, 55% yield, 99% purity) as a white solid. MS m/z (ESI) [M+H]+= 221.0. Step 2: To a solution of 2-(azetidin-1-yl)-5-bromo-thiazole 8.2 (0.25 g, 1.1 mmol, 1.0 eq) in THF (10 mL) was added n-BuLi (2.5 M, 1.0 mL, 2.2 eq) at – 60 °C. After stirring 0.5 h, the 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.32 g, 1.7 mmol, 0.35 mL, 1.5 eq) was added into the mixture at – 60 °C .Then, the mixture was stirred at – 60 °C for 2 h Attorney Docket No.: 185992002240 and heated to room temperature. The reaction mixture was added into saturated aqueous solution of ammonium chloride (20 mL) and extracted with ethyl acetate 45 mL (15 mL, three times). The combined organic layers were washed with brine 15 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give bor.2 (0.20 g, 0.38 mmol, 33% yield, 50% purity) as a brown solid. MS m/z (ESI) [M+H]+= 267.1. bor.3: tert-butyl N-methyl-N-[2-[[5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]
Figure imgf000234_0001
Figure imgf000234_0002
Step 1: To a solution of 5-bromopyridin-2-ol 9.1 (1.0 g, 5.8 mmol, 1.0 eq) and tert- butyl N-(2-hydroxyethyl)-N-methylcarbamate (1.2 g, 6.9 mmol, 1.2 eq) in THF (20 mL) was added triphenylphosphine (1.8 g, 6.9 mmol, 1.2 eq) and diisopropyl azodicarboxylate (1.4 g, 6.9 mmol, 1.3 mL, 1.2 eq) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (40 g column, Eluent of 0~15% EtOAc/PE gradient at 30 mL/min) to give tert-butyl N-[2-[(5-bromo-2-pyridyl) oxy] ethyl]-N-methylcarbamate 9.2 (1.0 g, 2.9 mmol, 50% yield, 95% purity) as colorless oil. MS m/z (ESI) [M-55]+= 241.0. Step 2: A mixture of tert-butyl N-[2-[(5-bromo-2-pyridyl)oxy]ethyl]-N-methyl- carbamate 9.2 (0.50 g, 1.5 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.42 g, 1.7 mmol, 1.1 eq), bis[3- (diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (0.11 g, 0.15 mmol, 0.10 eq), potassium acetate (0.30 g, 3.0 mmol, 2.0 eq) in dioxane (10 mL) was degassed and purged with nitrogen for 3 times at 25 °C. After stirring at 80 °C for 16 h under nitrogen atmosphere, the reaction mixture was concentrated under reduce pressure. The residue obtained was purified by Flash chromatography (12 g column, Eluent of 0~10% EtOAc/PE gradient at 50 mL/min) to give bor.3 (0.50 g, 1.15 mmol, 76% yield, 87% purity) as colorless oil. MS m/z (ESI) [M-100+H]+= 297.1. Attorney Docket No.: 185992002240 bor.4: tert-butyl N-cyclopropyl-N-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- pyridyl] oxy] ethyl] carbamate
Figure imgf000235_0001
Step 1: To a solution of 5-bromopyridin-2-ol 10.1 (2.0 g, 11.5 mmol, 1.0 eq), 2,2- diethoxyethanol (1.9 g, 14 mmol, 1.2 eq) in THF (20 mL) were added triphenylphosphine (3.6 g, 14 mmol, 1.2 eq) and diisopropyl azodiformate (2.8 g, 14 mmol, 1.2 eq) at 0 °C. After stirring at 20 °C for 12 h, the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (40 g column, Eluent of 0~40% EtOAc/PE gradient at 40 mL/min) to give 5-bromo-2-(2,2-diethoxyethoxy) pyridine 10.2 (3.0 g, 10 mmol, 90% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) d (ppm): 7.87 (d, J = 2.8 Hz, 1H) ,7.54 (dd, J = 10, 2.8 Hz, 1H), 6.38 (d, J = 9.8 Hz, 1H), 4.71 - 4.66 (m, 1H), 3.94 (d, J = 5.5 Hz, 2H), 3.70 - 3.55 (m, 4H), 1.05 (t, J = 7.0 Hz, 6H). Step 2: To a solution of 5-bromo-2-(2,2-diethoxyethoxy) pyridine 10.2 (2.8 g, 10 mmol, 1.0 eq) in acetonitrile (20 mL) was added hydrochloric acid (4 M, 6.0 mL, 2.5 eq) at 20 °C. The mixture was stirred at 20 °C for 4 h. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (30.0 mL, three times). The combined organic layers were washed with brine (10 mL, three times), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give 2-[(5-bromo-2-pyridyl) oxy] acetaldehyde 10.3 (2.2 g, crude) as an off-white solid. Step 3: To a solution of 2-[(5-bromo-2-pyridyl) oxy] acetaldehyde 10.3 (1.1 g, 5.1 mmol, 1.0 eq) and cyclopropanamine (0.26 g, 4.6 mmol, 0.90 eq) in methanol (15 mL) were added acetic acid (0.92 g, 15 mmol, 3.0 eq) and sodium cyanoborohydride (0.48 g, 7.6 mmol, 1.5 eq) at 20 °C. After stirring at 20 °C for 12 h, the reaction mixture was concentrated under reduced pressure. The residue obtained was diluted with water (15 mL) and then extracted with ethyl acetate (15 mL, three times). The combined organic phases were washed with brine (5.0 mL, three times), dried with anhydrous sodium sulfate, filtered and the filtrate was Attorney Docket No.: 185992002240 concentrated under reduced pressure to give N-[2-[(5-bromo-2- pyridyl)oxy]ethyl]cyclopropanamine 10.4 (0.80 g, 2.4 mmol, 47% yield, 77% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 259.1. Step 4: To a solution of N-[2-[(5-bromo-2-pyridyl)oxy]ethyl]cyclopropanamine 10.4 (0.80 g, 2.4 mmol, 1.0 eq) in
Figure imgf000236_0001
dimethylformamide (10 mL) were added triethylamine (0.73 g, 7.2 mmol, 1.0 mL, 3.0 eq) and tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (1.1 g, 4.8 mmol, 1.1 mL, 2.0 eq) at 20 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (20.0 mL, three times). The combined organic phases were washed with brine (10 mL, three times), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (12 g column, Eluent of 0~25% EtOAc/PE gradient at 40 mL/min) to give tert-butyl N-[2-[(5-bromo-2-pyridyl) oxy] ethyl]-N-cyclopropyl-carbamate 10.5 (0.60 g, 1.4 mmol, 60% yield, 86% purity) as a yellow solid. MS m/z (ESI) [M-100]+ = 257.2. Step 5: To a mixture of tert-butyl N-[2-[(5-bromo-2-pyridyl)oxy]ethyl]-N- cyclopropyl-carbamate 10.5 (0.60 g, 1.4 mmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (0.44 g, 1.7 mmol, 1.2 eq) in dioxane (10 mL) were added 1,1-bis(diphenylphosphino)ferrocene palladium(II)dichloride (53 mg, 0.07 mmol, 0.05 eq) and potassium acetate (0.28 g, 2.9 mmol, 2.0 eq) at 25 °C. The mixture was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 60 °C for 4 h under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (10 mL), then the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (12 g column, Eluent of 0~25% EtOAc/PE gradient at 40 mL/min) to give bor.4 (0.40 g, 0.73 mmol, 51% yield, 74% purity) as a brown solid. MS m/z (ESI) [M+H]+ = 405.3. bor.5: tert-butyl N-[1-methyl-2-oxo-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- pyridyl] ethyl] carbamate
Figure imgf000236_0002
Attorney Docket No.: 185992002240 Step 1: To a solution of 2-(tert-butoxycarbonylamino) propanoic acid 11.1 (10 g, 53 mmol, 1.0 eq) in DMF (100 mL) was added HATU (25 g, 66 mmol, 1.2 eq), the reaction mixture was stirred at 25 °C for 10 min. Then to the mixture was added DIEA (19 g, 0.14 mol, 25 mL, 2.7 eq) and N-methoxymethanamine (6.0 g, 62 mmol, 1.2 eq, HCl). The mixture was stirred at 25 °C for another 5 h. The reaction mixture was extracted with EtOAc (400 mL) and H2O (300 mL). The combined organic layers were washed with saturated aqueous NH4Cl (300 mL), saturated aqueous NaHCO3 (300 mL) and saturated aqueous NaCl (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (80 g column, Eluent of 0~50% EtOAc/PE gradient at 100 mL/min) to give tert-butyl N-[2-[methoxy(methyl)amino]-1-methyl-2-oxo- ethyl] carbamate 11.2 (9.0 g, 37 mmol, 70% yield, 95% purity) as a white solid. Step 2: To a solution of 5-bromo-2-iodo-pyridine 11.3 (9.7 g, 34 mmol, 1.0 eq) in THF (150 mL) was added tert-butyl N-[2-[methoxy(methyl)amino]-1-methyl-2-oxo- ethyl]carbamate (8.0 g, 34 mmol, 1.0 eq) , the reaction mixture was degassed and purged with N2 for three times, then i-PrMgCl (2 M, 35 mL, 2.0 eq) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was quenched with saturated aqueous NH4Cl (300 mL) and extracted with EtOAc (500 mL, twice). The combined organic layers were washed with saturated aqueous NaCl (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (80 g column, Eluent of 0~9% EtOAc/PE gradient at 100 mL/min) to give the desired compound as a yellow solid, which was further purified by reversed-phase MPLC (0.1%FA condition) to give tert-butyl N-[2-(5-bromo-2- pyridyl)-1-methyl-2-oxo-ethyl]carbamate 11.4 (4.0 g, 12 mmol, 36% yield, 100% purity) as a white solid. Step 3: To a solution of tert-butyl N-[2-(5-bromo-2-pyridyl)-1-methyl-2-oxo- ethyl]carbamate 11.4 (0.36 g, 1.1 mmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.44 g, 1.7 mmol, 1.6 eq) in dioxane (5.0 mL) was added Pd(dppf)Cl2 (72 mg, 98 μmol, 0.09 eq) and KOAc (0.33 g, 3.3 mmol, 3.0 eq). The reaction mixture was degassed and purged with N2 for three times. The mixture was stirred at 80 °C for 5 h under N2 atmosphere. After filtration and concentration under reduced pressure the crude product bor.5 (0.42 g, crude) was directly used into the next step without further purification as a black liquid. Attorney Docket No.: 185992002240 bor.6: [6-(azetidin-1-yl)-3-pyridyl] boronic acid
Figure imgf000238_0001
To a solution of 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine 12.1 (4.5 g, 20 mmol, 1.0 eq) and azetidine (2.3 g, 24 mmol, 2.7 mL, 1.2 eq, HCl) in DMSO (40 mL) was added K2CO3 (8.4 g, 61 mmol, 3.0 eq) at 25 °C. The mixture was stirred at 100 °C for 16 h. Then the mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL, three times). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue obtained was purified by prep-HPLC 3 (gradient: 0%-30% ACN over 10 min) to give bor.6 (2.2 g, 12 mmol, 61% yield, 99% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 178.9. bor.7: (6-(4-((tert-butoxycarbonyl) alanyl) piperazin-1-yl) pyridin-3-yl) boronic acid
Figure imgf000238_0002
Step 1: To a solution of tert-butyl 4-(5-bromo-2-pyridyl) piperazine-1-carboxylate 13.1 (1.0 g, 2.9 mmol, 1.0 eq) in dioxane (0.5 mL) was added HCl/dioxane (2.0 M, 2.0 mL) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 1-(5-bromo-2-pyridyl) piperazine 13.2 (0.80 g, 2.8 mmol, 96% yield, 98% purity, HCl). MS m/z (ESI) [M+H]+ = 242.0. Step 2: To a solution of 1-(5-bromo-2-pyridyl)piperazine 13.2 (0.80 g, 2.9 mmol, 1.0 eq, HCl) in DMF (3.0 mL) was added 2-(tert-butoxycarbonylamino)propanoic acid (0.65 g, 3.4 mmol, 1.2 eq), HATU (2.2 g, 5.7 mmol, 2.0 eq) and DIEA (1.5 g, 11 mmol, 2.0 mL, 4 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl N-[2-[4-(5-bromo-2-pyridyl) piperazin-1-yl]-1-methyl-2-oxo-ethyl] carbamate 13.3 (1.1 g, 2.6 mmol, 92% yield, 99% purity). MS m/z (ESI) [M+H] + = 413.1. Step 3: A mixture of tert-butyl N-[2-[4-(5-bromo-2-pyridyl)piperazin-1-yl]-1-methyl- 2-oxo-ethyl]carbamate 13.3 (1.1 g, 2.7 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5- Attorney Docket No.: 185992002240 tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.0 g, 4.0 mmol, 1.5 eq), Pd(dppf)Cl2 (0.20 g, 0.27 mmol, 0.10 eq) and AcOK (0.79 g, 8.0 mmol, 3.0 eq) in dioxane (3.0 mL) was degassed and purged with N2 three times at 25 °C. Then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (35 mL, three times). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The new residue obtained was purified by prep-HPLC 2 (gradient:10%-40% ACN over 15 min) to give bor.7 (0.48 g, 1.3 mmol, 48% yield, 100% purity). MS m/z (ESI) [M+H]+ = 379.2. bor.8: tert-butyl (3-methyl-1-oxo-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) amino) butan-2-yl) carbamate
Figure imgf000239_0001
To a solution of 4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline 14.1 (1.0 g, 4.6 mmol, 1.0 eq) and 2-(tert-butoxycarbonylamino) -3-methyl-butanoic acid (1.0 g, 4.6 mmol, 1.0 eq) in DMF (20 mL) was added HATU (2.6 g, 6.9 mmol, 1.5 eq) and DIEA (2.0 g, 15 mmol, 2.7 mL, 3.4 eq) in turns, then the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with EtOAc (50 mL), washed with sat.NH4Cl (50 mL, twice)., saturated aqueous NaHCO3 (50 mL, twice), brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give crude material. The residue obtained was purified by Flash chromatography (40 g Column, Eluent of 0 to 40% EtOAc/PE gradient at 40 mL/min) to give bor.8 (1.2 g, 2.2 mmol, 48% yield, 76% purity) as white solid. MS m/z (ESI) [M+H]+ = 419.3. bor.9: tert-butyl (1-oxo-1-(4- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-
Figure imgf000239_0002
yl)carbamate
Figure imgf000239_0003
Step 1: To a solution of 1-bromo-4-iodo-benzene (0.5 g, 1.77 mmol, 1 eq) and tert- butyl (1-oxopropan-2-yl)carbamate (306.13 mg, 1.77 mmol, 1 eq) in THF (10 mL) was added Attorney Docket No.: 185992002240 i-PrMgCl (1.3 M, 2.72 mL, 2 eq) at 0 °C .The mixture was stirred at 25 °C for 2 hours under N2 atmosphere. The reaction mixture was quenched by saturated ammonium chloride aqueous solution (30 mL) at 0°C, and then extracted with ethyl acetate (15 mL, three times). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 40mL/min) to give tert-butyl (1- (4-bromophenyl)-1-hydroxypropan-2-yl)carbamate (380 mg, 1.04 mmol, 58.60% yield, 90% purity) as colorless oil . 1H NMR (400 MHz, CDCl3) d (ppm): 7.48 - 7.45 (m, 2H), 7.22 (d, J = 8.3 Hz, 2H), 4.71 - 4.64 (m, 1H), 4.54 ( d, J = 5.5 Hz, 1H), 3.86 - 3.75 (m, 1H), 3.61 - 3.51 (m, 1H), 1.47 - 1.40 (m, 12H), 1.08 ( d, J = 6.7 Hz, 2H). Step 2: To a solution of tert-butyl (1-(4-bromophenyl)-1-hydroxypropan-2- yl)carbamate (0.38 g, 1.15 mmol, 1 eq) in DCM (4 mL) was added (1,1-diacetoxy-3-oxo-1,2- benziodoxol-1-yl) acetate (0.98 g, 2.30 mmol, 713.05 μL, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give tert-butyl (1-(4-bromophenyl)-1-oxopropan-2-yl)carbamate (0.27 g, 806.21 μmol, 70% yield, 98% purity) was obtained as a white solid. MS m/z (ESI) [M+H]+ = 229. Step 3: A mixture of tert-butyl (1-(4-bromophenyl)-1-oxopropan-2-yl)carbamate (0.27 mg, 822.67 μmol, 1 eq) , 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (0.313 g, 1.23 mmol, 1.5 eq), KOAc (0.24 g, 2.47 mmol, 3 eq) and Pd(dppf)Cl2 (0.06 g, 82.27 μmol, 0.1 eq) in dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 hours under N2 atmosphere. The reaction mixture was used next step directly without purification. bor.9 (0.31 g, crude) was obtained as black oil. bor.10: tert-butyl N-methyl-N-[2-[methyl-[5-(4,4,5,5-tetramethyl- dioxaborolan-2-yl)-2-
Figure imgf000240_0001
pyridyl]amino]ethyl]carbamate
Figure imgf000240_0002
Attorney Docket No.: 185992002240 To a solution of 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1 g, 4.48 mmol, 1 eq) and tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (0.84 g, 4.48 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (1.86 g, 13.45 mmol, 3 eq) at 25 °C. The mixture was stirred at 80 °C for 16 hours. The mixture was diluted with water (100mL) and extracted with ethyl acetate (100 mL, three times). The organic phase was washed with brine (200 mL, three times), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 3/1). bor.10 (300 mg, 689.99 μmol, 15.39% yield, 90% purity) was obtained as a white solid. MS m/z (ESI) [M-82+H]+ = 310.2 (boric acid). bor.11: tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]azetidine-1- carboxylate
Figure imgf000241_0001
To a solution of tert-butyl 3-iodoazetidine-1-carboxylate (1.00 g, 3.53 mmol, 1.00 eq) and K2CO3 (0.98 g, 7.06 mmol, 2.00 eq) in DMF (10.0 mL) was added 4-(4,4,5,5- tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (0.85 g, 3.89 mmol, 1.10 eq) at 20 °C. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate= 10/1 to 1/1) to give bor.11 (1.00 g, 2.66 mmol, 75.4% yield) as a yellow solid. MS m/z (ESI) [M-56+H]+ = 320.2. bor.12: tert-butyl 3-[4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1- carboxylate
Figure imgf000241_0002
To a solution of 4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (1.00 g, 4.54 mmol, 1.00 eq), tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.02 g, 5.45 mmol, 1.20 eq) and PPh3 (1.79 g, 6.82 mmol, 1.50 eq) in THF (15.0 mL) was added (3E)-3- (dimethylcarbamoylimino)-1,1-dimethyl-urea (1.17 g, 6.82 mmol, 1.50 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was quenched by addition of water (15.0 mL) at 20 °C, and then extracted with EtOAc (15.0 mL, three times). Attorney Docket No.: 185992002240 The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 2/1) to give bor.12 (1.00 g, 2.57 mmol, 56.5% yield) as a white solid. MS m/z (ESI) = 334.1. bor.13: tert-butyl 3-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- pyridyl]oxymethyl]azetidine-1-carboxylate
Figure imgf000242_0001
Step 1: To a solution of 5-bromopyridin-2-ol (1 g, 5.75 mmol, 1 eq), tert-butyl 3- (hydroxymethyl)azetidine-1-carboxylate (1.61 g, 8.62 mmol, 1.5 eq) in THF (10 mL) was added DIAD (1.74 g, 8.62 mmol, 1.67 mL, 1.5 eq) and PPh3 (2.26 g, 8.62 mmol, 1.5 eq) at 0°C. After stirring at 25°C for 16 hours, the reaction mixture was added into water(10 mL) and extracted with ethyl acetate30 mL (10 mL, three times). The combined organic layers were washed withbrine (10 mL, three times), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~15% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give tert-butyl 3-[(5-bromo- 2-pyridyl)oxymethyl]azetidine-1-carboxylate (1.2 g, 3.15 mmol, 54.75% yield, 90% purity) as colorless oil. MS m/z (ESI) [M+H]+ = 343.1. Step 2: To a solution of tert-butyl 3-[(5-bromo-2-pyridyl)oxymethyl]azetidine-1- carboxylate (0.5 g, 1.46 mmol, 1 eq) , 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.55 g, 2.19 mmol, 1.5 eq) in dioxane (4 mL) was added Pd(dppf)Cl2 (0.01 g, 145.68 μmol, 0.1 eq) and AcOK (0.43 g, 4.37 mmol, 3 eq) at 25°C. After stirring at 80°C for 16 hours, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0~22% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give bor.13 (0.5 g, 1.15 mmol, 79.15% yield, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 391.3. Attorney Docket No.: 185992002240 bor.14: tert-butyl N-methyl-N-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]sulfanylethyl]carbamate
Figure imgf000243_0001
A mixture of tert-butyl N-[2-(4-bromophenyl)sulfanylethyl]-N-methyl-carbamate (1.7 g, 4.91 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (1.87 g, 7.36 mmol, 1.5 eq), Pd(dppf)Cl2 (359 mg, 490.64 μmol, 0.1 eq) and KOAc (1.45 g, 14.73 mmol, 3 eq) in dioxane (20 mL) was stirred at 80 °C for 12hours under N2. The mixture was concentrated and the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give bor.14 (1.9 g, 4.35 mmol, 88.55% yield, 90% purity) as light yellow oil. 1H NMR (400 MHz, DMSO-d6) d (ppm): 7.58 (d, J = 8.1 Hz, 2H), 7.33 (br d, J = 7.0 Hz, 2H), 3.37 (br d, J = 6.3 Hz, 2H), 3.14 (br t, J = 6.7 Hz, 2H), 2.78 (br s, 3H), 1.42 - 1.32 (m, 9H), 1.28 (s, 12H). MS m/z (ESI) [M-100+H]+ = 294.1. bor.15: trimethyl-[2-[[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy] imidazol- 1-yl]methoxy]ethyl]silane
Figure imgf000243_0002
Step 1: To a solution of 2-[(4-iodoimidazol-1-yl)methoxy]ethyl-trimethyl-silane (5.00 g, 15.42 mmol, 0.5 eq) in dioxane (70 mL) was added 4-bromophenol (8.07 g, 46.67 mmol, 1.5 eq) , Cs2CO3 (30.00 g, 92.08 mmol, 2.96 eq), bis[(Z)-1-methyl-3-oxo-but-1-enoxy]copper (800 mg, 3.06 mmol, 0.1 eq), then the resulting mixture was purged with N2 three times and stirred at 120°C for 12 hours. The reaction mixture was partitioned between EtOAc(400 mL) and water(250 mL), washed with brine(200 mL), died over Na2SO4, filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give a yellow solid. The yellow solid was purified by reversed-phase HPLC(0.1% FA condition) to give the 2-[[4-(4- bromophenoxy)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (1.5 g, 3.76 mmol, 12.10% yield, 92.7% purity) as a white solid. MS m/z (ESI) [M+H]+= 371.1. Attorney Docket No.: 185992002240 Step 2: To a solution of 2-[[4-(4-bromophenoxy)imidazol-1-yl]methoxy]ethyl- trimethyl-silane (1.2 g, 3.25 mmol, 1 eq) in dioxane (15 mL) was added KOAc (960.00 mg, 9.78 mmol, 3.01 eq) , Pd(dppf)Cl2 (360.00 mg, 492.00 μmol, 1.51e-1 eq) , 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1 g, 3.94 mmol, 1.21 eq), then the resulting mixture was purged with N2 three timesand stirred at 80°C for 12 hours. The reaction mixture was filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give bor.15 (1 g, 2.17 mmol, 66.67% yield, 90.2% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 417.2. tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanamine
Figure imgf000244_0001
Figure imgf000244_0002
To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (10 g, 45.44 mmol, 1 eq), 2-(dimethylamino)ethanol (6.08 g, 68.16 mmol, 6.84 mL, 1.5 eq) and PPh3 (21.45 g, 81.79 mmol, 1.8 eq) in THF (180 mL) was added DIAD (16.54 g, 81.79 mmol, 15.86 mL, 1.8 eq) at 0 °C. The mixture was stirred at 0~25 °C for 12hours under N2. The mixture was concentrated and the residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give a crude product. The crude product was triturated with PE/EtOAc (v/v = 2/1, 60 ml) and then purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~35% THF/Petroleum ether gradient @ 100 mL/min). The product obtained was triturated with PE/EtOAc (v/v = 2/1, 21 ml) to give bor.16 (3.1 g, 3.19 mmol, 7.03% yield, 30% purity) as brown oil. 1H NMR (400 MHz, DMSO-d6) d (ppm): 7.57 - 7.51 (m, 2H), 6.92 (d, J = 8.5 Hz, 2H), 4.09 - 4.03 (m, 2H), 2.61 (t, J = 5.8 Hz, 2H), 2.20 (s, 6H), 1.22 - 1.16 (m, 12H). MS m/z (ESI) [M+H]+= 292.2. bor.17: tert-butyl 3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]methyl]azetidine-1-carboxylate
Figure imgf000244_0003
Attorney Docket No.: 185992002240 To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5 g, 22.72 mmol, 1 eq) tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (4.4 g, 23.50 mmol, 1.03 eq) and PPh3 (9 g, 34.31 mmol, 1.51 eq) in THF (60 mL) was added DIAD (7.30 g, 36.11 mmol, 7 mL, 1.59 eq) at 0 °C under N2, The reaction solution was stirred at 25°C for 12 hours. The reaction mixture was partitioned between EtOAc (1 L) and water (500 mL), washed with brine (400 mL), died over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give a residue. The residue was purified by reversed-phase HPLC ( 0.1% FA condition) to bor.17 (5 g, 10.53 mmol, 46.36% yield, 82% purity) as a red oil. MS m/z (ESI) [M+Na]+= 412.2. Synthesis of amine intermediates amine.1: 1, 2, 3, 3a, 4, 5, 7, 7a-octahydropyrrolo [3, 4-c] pyridin-6-one
Figure imgf000245_0001
Step 1: Tert-butyl 5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate 15.1 (5.0 g, 22 mmol, 1.0 eq) was added to HCl/dioxane (2 M, 40 mL, 3.6 eq). The reaction solution was stirred at 25 °C for 1 h. The solution was concentrated under vacuum to give 2,3,3a,4,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-one 15.2 (5.0 g, crude, HCl) as a yellow solid which was used for next step without further purification. Step 2: To a solution of 2,3,3a,4,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-one 15.2 (3.6 g, 22 mmol, 1.0 eq, HCl) and TEA (7.3 g, 72 mmol, 10 mL, 3.2 eq) in DCM (40 mL) was added CbzCl (4.6 g, 27 mmol, 3.8 mL, 1.2 eq) at 0 °C, The reaction solution was stirred at 25 °C for 1 h. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The combine organic phases were washed by sat. NaCl (50 mL). The combined organic layers were dried over Na2SO4 and evaporated to give a crude material. The residue obtained was purified by Flash chromatography (12 g column, Eluent of 0~20% EtOAc/PE gradient at 40 mL/min) to afford benzyl 5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2- carboxylate 15.3 (1.2 g, 3.4 mmol, 15% yield, 73% purity) as a light-yellow oil. Attorney Docket No.: 185992002240 Step 3: To a solution of benzyl 5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2- carboxylate 15.3 (1.2 g, 4.6 mmol, 1.0 eq) in MeOH (20 mL) /H2O (5 mL) was added NH2OH.HCl (0.72 g, 10 mmol, 2.2 eq) and NaOAc (1.1 g, 13 mmol, 2.8 eq). The reaction solution was stirred at 25 °C for 1 h. The residue was partitioned between EtOAc (500 mL) and water (500 mL). The combine organic phases were washed by sat. NaCl (500 mL). The combined organic layers were dried over Na2SO4 and evaporated to give a crude material. The residue obtained was purified by Flash chromatography (12 g column, Eluent of 0~20% EtOAc/PE gradient at 40 mL/min) to afford benzyl 5-hydroxyimino-1,3,3a,4,6,6a- hexahydrocyclopenta[c]pyrrole-2-carboxylate 15.4 (1.2 g, 4.4 mmol, 95% yield) as a light- yellow oil. 1H NMR (400 MHz, CDCl3) d (ppm): 7.38 - 7.33 (m, 5H), 5.14 (d, J = 4.9 Hz, 2H), 3.71 - 3.63 (m, 2H), 3.33 - 3.18 (m, 2H), 2.83 - 2.65 (m, 4H), 2.44 - 2.34 (m, 2H). Step 4: To a solution of benzyl 5-hydroxyimino-1,3,3a,4,6,6a- hexahydrocyclopenta[c]pyrrole-2-carboxylate 15.4 (1.2 g, 4.4 mmol, 1.0 eq) in THF (10 mL) was added SOCl2 (1.6 g, 14 mmol, 1.0 mL, 3.2 eq) at 0 °C. The solution was stirred at 25 °C for 2 h. The residue was partitioned between EtOAc (500 mL) and water (500 mL). The combined organic phases were washed by sat. NaCl (500 mL). The combined organic layers were dried over Na2SO4 and evaporated to give a crude material. The residue obtained was purified by prep-HPLC 2 (gradient: 23%-53% ACN over 15 min). After Prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give benzyl 6-oxo-3,3a,4,5,7,7a-hexahydro-1H-pyrrolo[3,4-c] pyridine-2-carboxylate 15.5 (0.60 g, 2.2 mmol, 50% yield, 100% purity) as a yellow oil. 1H NMR (400 MHz, CDCl3) d (ppm): 7.40 - 7.37 (m, 5H), 5.16 (s, 2H), 3.79 - 3.62 (m, 3H), 3.45 - 3.28 (m, 3H), 2.94 - 2.60 (m, 3H), 2.47 (br dd, J = 3.7, 17.9 Hz, 1H). MS m/z (ESI) [M+H] + = 275.2. Step 5: To a solution of Pd/C (20 mg, 10% purity) in EtOAc (5.0 mL) was added benzyl 6-oxo-3, 3a, 4, 5, 7, 7a-hexahydro-1H-pyrrolo[3, 4-c]pyridine-2-carboxylate 15.5 (0.10 g, 0.36 mmol, 1.0 eq) under N2. The reaction solution was degassed and purged under H2 for three times. The reaction solution was stirred at 25 °C for 12 h. The reaction solution was filtered, and the filtrate was concentrated under vacuum to give 1, 2, 3, 3a, 4, 5, 7, 7a- octahydropyrrolo [3, 4-c] pyridin-6-one amine.1 (50 mg, crude) as a yellow oil was used for next step without purification. Attorney Docket No.: 185992002240 Amine.2: tert-butyl 9,9-difluoro-2,7-diazaspiro [4.5] decane-7-carboxylate Amide.2: tert-butyl 9,9-difluoro-1-oxo-2,7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000247_0001
Step 1: A solution of 1-(tert-butyl) 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate 16.1 (0.80 g, 2.9 mmol, 1.0 eq) in THF (10 mL) was degassed and purged with nitrogen three times. To the mixture was added LiHMDS (1 M, 4.50 mL, 1.6 eq) at -78 °C. After stirring at - 78 °C for 0.5 h, was added 2-bromoacetonitrile (0.70 g, 5.8 mmol, 2.0 eq) at -78 °C. Then the mixture was stirred at 25 °C for another 1.5 h under nitrogen atmosphere. The reaction mixture was quenched by saturated ammonium chloride aqueous solution (20 mL) and saturated sodium bicarbonate solution (20 mL). The mixture was then extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (3 × 10 mL), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by Flash chromatography 2 (12 g column, Eluent of 0 to 20% EtOAc/PE gradient at 30 mL/min) to give 1-(tert-butyl) 3-methyl 3-(cyanomethyl)-5,5- difluoropiperidine-1,3-dicarboxylate 16.2 (0.90 g, 2.8 mmol, 99% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 3.87 - 3.74 (m, 2H), 3.71 (s, 3H), 3.67 - 3.53 (m, 2H), 2.84 (s, 2H), 2.63 - 2.52 (m, 1H), 2.34 - 2.20 (m, 1H), 1.42 (s, 9H). Step 2: To a solution of 1-(tert-butyl) 3-methyl 3-(cyanomethyl)-5,5- difluoropiperidine-1,3-dicarboxylate 16.2 (0.90 g, 2.8 mmol, 1.0 eq) in MeOH (20 mL) was added Raney-Ni (0.10 g) at 25 °C in a high-pressure reaction reactor. The mixture was stirred at 25 °C for under hydrogen (50 Psi) for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 7,7-difluoro-1-oxo-2,9- diazaspiro [4.5] decane-9-carboxylate 16.3 (0.75 g, 2.6 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.94 (s, 1H), 4.28 - 4.05 (m, 1H), 3.95 - 3.73 (m, 1H), 3.30 - 3.09 (m, 3H), 2.88 - 2.65 (m, 1H), 2.31 - 2.13 (m, 1H), 2.04 – 1.83 (m, 3H), 1.41 (s, 9H). Step 3: To a solution of tert-butyl 7,7-difluoro-1-oxo-2,9-diazaspiro [4.5] decane-9- carboxylate 16.3 (0.70 g, 2.4 mmol, 1.0 eq) in THF (10 mL) was added BH3/Me2S (10 M, 3.0 mL, 12 eq) at 25 °C. The mixture was stirred at 50 °C for 3 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (30 mL) and then extracted Attorney Docket No.: 185992002240 with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (3 × 10 mL), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a mixture of amine.2 and amide.2 (650 mg, crude) as a white solid. amine.3: cis-5-methyloctahydro-1H-pyrrolo[3,4-c]pyridine
Figure imgf000248_0001
To a solution of tert-butyl cis-octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (1.5 g, 5.71 mmol, 1 eq, HCl salt) in THF (30 mL) was added dropwise LiAlH4 (2.5 M, 7 mL, 3 eq) at 0 °C over 1 min. After addition, the mixture was stirred at 50 °C for 16 hours under N2 atmosphere. The reaction mixture was added Na2SO4 (2 g) and water (0.5 mL) at 20 °C, and then diluted with EtOAc (20 mL) filtered and concentrated under reduced pressure to give amine.3 (800 mg, crude) as yellow oil. 1H NMR (400 MHz, CDCl3) d (ppm): 3.06 - 2.52 (m, 8H), 2.24 - 2.22 (m, 3H), 1.81 - 1.60 (m, 4H). amine.4: N-methylpyrrolidine-3-carboxamide
Figure imgf000248_0002
Step 1: To a solution of 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (2 g, 9.29 mmol, 1 eq) in DMF (20 mL) was added methanamine;hydrochloride (750 mg, 11.11 mmol, 1.2 eq), HATU (5.30 g, 13.94 mmol, 1.5 eq) and DIEA (3.60 g, 27.88 mmol, 4.86 mL, 3 eq) at 25°C.The mixture was stirred at 25 °C for 16 hours . The reaction mixture was diluted with water (35 mL) and extracted with ethyl acetate (25 mL, three times). The combined organic layers were washed with brine (30 mL) and saturated NaHCO3 solution (30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 3- (methylcarbamoyl)pyrrolidine-1-carboxylate (950 mg, crude). 1H NMR (400 MHz, DMSO- d6) d (ppm): 7.87 (s, 1H), 3.44 - 3.33 (m, 2H), 3.24 - 3.15 (m, 2H), 2.91 - 2.80 (m, 1H), 2.57 (d, J = 4.5 Hz, 3H), 1.98 - 1.81 (m, 2H), 1.39 (s, 9H). Step 2: To a solution of tert-butyl 3-(methylcarbamoyl)pyrrolidine-1-carboxylate (950 mg, 4.16 mmol, 1 eq) in MeOH (1 mL) was added HCl/MeOH (2 M, 3 mL) at 25°C .The Attorney Docket No.: 185992002240 mixture was stirred at 25 °C for 4 hours . The reaction mixture was filtered and concentrated under reduced pressure to give amine.4 (700 mg, crude). 1H NMR (400 MHz, DMSO-d6) d (ppm): 9.56 - 9.31 (m, 1H), 9.17 (d, J = 4.9 Hz, 1H), 8.19 (d, J = 3.1 Hz, 1H), 3.34 - 3.25 (m, 1H), 3.20 - 3.12 (m, 3H), 3.01 (q, J = 7.7 Hz, 1H), 2.59 (d, J = 4.6 Hz, 3H), 2.16 - 2.05 (m, 1H), 1.96 - 1.85 (m, 1H). amine.5: 3-(difluoromethoxy)pyrrolidine
Figure imgf000249_0001
Step 1: To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1 g, 5.34 mmol, 1 eq) in MeCN (20 mL) was added CuI (250 mg, 1.31 mmol, 0.25 eq) , 2,2-difluoro-2- fluorosulfonyl-acetic acid (2.30 g, 12.90 mmol, 1.33 mL, 2.42 eq), 2,2-difluoro-2- fluorosulfonyl-acetic acid (2.30 g, 12.90 mmol, 1.33 mL, 2.42 eq) , then the resulting mixture was stirred at 60°C for 2 hours. The reaction mixture was partitioned between EtOAc (150 mL) and water (80 mL), washed with brine (70 mL), died over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give tert-butyl 3- (difluoromethoxy)pyrrolidine-1-carboxylate (400 mg, 1.69 mmol, 31.57% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) d (ppm): 6.45 - 6.01 (m, 1H), 3.63 - 3.36 (m, 4H), 2.14 - 2.05 (m, 2H), 1.47 (s, 9H). Step 2: To a solution of tert-butyl 3-(difluoromethoxy)pyrrolidine-1-carboxylate (300 mg, 1.26 mmol, 1 eq) in DCM (2 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 5.32 eq), then resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and evaporated under reduced pressure to give the amine.5 (200 mg, crude) as colourless oil which was used without further purification. Attorney Docket No.: 185992002240 amine.6:  cis-octahydro-4H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000250_0001
Step 1: To a solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (20 g, 93.80 mmol, 1 eq) and DIEA (22.26 g, 172.24 mmol, 30 mL, 1.84 eq) in DCM (200 mL) was added trifluoromethylsulfonyl trifluoromethanesulfonate (31 g, 109.87 mmol, 18.13 mL, 1.17 eq) at 0 °C. The reaction solution was stirred at 0 °C for another 30 min. The residue was partitioned between EtOAc (500 mL) and water (500 mL). The organic phase was washed by saturated NaCl (50 mL) . The combined organic layers were dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% eToaC/Petroleum ether gradient @ 40 mL/min) to afford tert-butyl 6-oxo-4-(trifluoromethylsulfonyloxy)-2,3-dihydropyridine-1- carboxylate (28 g, 81.09 mmol, 86.45% yield) as a yellow oil. 1H NMR (400 MHz, DMSO- d6) d (ppm): 6.02 (s, 1H), 3.99 (t, J = 6.6 Hz, 2H), 2.77 (t, J = 6.5 Hz, 2H), 1.55 (s, 9H). Step 2: Under nitrogen, to a solution of tert-butyl 6-oxo-4- (trifluoromethylsulfonyloxy)-2,3-dihydropyridine-1-carboxylate (26 g, 75.30 mmol, 1 eq), Pd(OAc)2 (3.40 g, 15.14 mmol, 2.01e-1 eq) , and PPh3 (7.80 g, 29.74 mmol, 3.95e- 1 eq) in DMF (300 mL) was added Et3SiH (17.47 g, 150.26 mmol, 24 mL, 2 eq) at 0 °C. The mixture was then stirred at 25 °C for 30 minutes. The residue was partitioned between EtOAc (500 mL) and water (500 mL). The organic phase was washed by saturated NaCl (50 mL). The combined organic layers were dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% EtOAc/Petroleum ether gradient @ 40 mL/min) to afford tert-butyl 6-oxo-2,3-dihydropyridine-1-carboxylate (10 g, 50.70 mmol, 67.33% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) d (ppm): 6.86 - 6.67 (m, 1H), 6.03 - 5.85 (m, 1H), 3.86 (dt, J = 3.2, 6.4 Hz, 2H), 2.41 (td, J = 2.0, 4.2 Hz, 2H), 1.54 (d, J = 3.4 Hz, 9H). Attorney Docket No.: 185992002240 Step 3: To a solution of tert-butyl 6-oxo-2,3-dihydropyridine-1-carboxylate (10 g, 50.70 mmol, 1 eq) in MeCN (100 mL) was added N-(methoxymethyl)-1-phenyl-N- (trimethylsilylmethyl)methanamine (24 g, 101.09 mmol, 1.99 eq). The reaction solution was stirred at 25 °C for 12 hours. The reaction solution concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% THF/Petroleum ether gradient @ 100 mL/min) to afford tert-butyl cis-2-benzyl-4-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (16 g, 48.42 mmol, 95.51% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) d (ppm): 7.34 - 7.23 (m, 5H), 3.95 (ddd, J = 3.1, 6.2, 13.1 Hz, 1H), 3.61 - 3.43 (m, 3H), 3.14 - 3.04 (m, 1H), 2.97 - 2.77 (m, 3H), 2.69 - 2.54 (m, 1H), 2.21 (dd, J = 6.1, 9.2 Hz, 1H), 2.00 - 1.87 (m, 1H), 1.60 - 1.47 (m, 10H). Step 4: To a solution of tert-butyl cis-2-benzyl-4-oxooctahydro-5H-pyrrolo[3,4- c]pyridine-5-carboxylate (8 g, 24.21 mmol, 1 eq) in MeOH (300 mL) was added Pd/C (1 g, 10% purity and Pd(OH)2 (1 g, 20% purity) under N2, The reaction solution was degassed and purged under H2 for three times, The reaction solution was stirred at 40 °C for 3 hours. The reaction solution was filtered and filtrate was concentrated under vacuum to give tert-butyl cis-4-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (4.8 g, crude) as a yellow oil which was used for next step without further confirmed. Step 5: To a solution of tert-butyl cis-4-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5- carboxylate (4.8 g, 19.98 mmol, 1 eq) in DCM (50 mL) was added (Boc)2O (5.23 g, 23.97 mmol, 5.51 mL, 1.2 eq) ,TEA (6.54 g, 64.66 mmol, 9 mL, 3.24 eq) and DMAP (250 mg, 2.05 mmol, 0.1 eq) ,The reaction solution was stirred at 25 °C for 1 hour. The residue was partitioned between EtOAc (300 mL) and water (300 mL). The organic phase was washed by saturated NaCl (300 mL) . The combined organic layers were dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% THF/Petroleum ether gradient @ 100 mL/min) to afford di-tert-butyl cis-4-oxohexahydro-2H-pyrrolo[3,4-c]pyridine-2,5(3H)- dicarboxylate (5.5 g, 14.38 mmol, 71.99% yield, 89% purity) as a yellow oil. MS m/z (ESI) [M+Na]+= 363.1. Step 6: Di-tert-butyl cis-4-oxohexahydro-2H-pyrrolo[3,4-c]pyridine-2,5(3H)- dicarboxylate (5.5 g, 16.16 mmol, 1 eq) was added to HCl/dioxane (2 M, 50 mL, 6.19 eq). The reaction solution was stirred at 25 °C for 1 hour. The reaction solution was concentrated Attorney Docket No.: 185992002240 under vacuum to give amine.6 (3 g, crude, HCl) as a white solid which was used for next step without further purification. amine.7: cis-5-methyloctahydro-4H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000252_0001
Step 1: To a solution of tert-butyl cis-4-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5- carboxylate (13.6 g, 56.60 mmol, 1 eq) in DCM (150 mL) was added CbzCl (9.80 g, 57.44 mmol, 8.2 mL, 1.01 eq) and TEA (14.54 g, 143.69 mmol, 20 mL, 2.54 eq). The reaction solution was stirred at 25 °C for 1 hour. The mixture was diluted with water (60 ml), and then extracted with EtOAc (50 mL, twice). The combined organic phase was washed with brine (50 ml, three times), dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~3% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give 2-benzyl 5-(tert-butyl) cis-4-oxohexahydro-2H-pyrrolo[3,4-c]pyridine-2,5(3H)-dicarboxylate (6 g, 14.74 mmol, 26.05% yield, 92% purity) as a colorless oil. MS m/z (ESI) [M+Na]+= 397.1. Step 2: 2-benzyl 5-(tert-butyl) cis-4-oxohexahydro-2H-pyrrolo[3,4-c]pyridine- 2,5(3H)-dicarboxylate (5 g, 13.35 mmol, 1 eq) was added to HCl/dioxane (2 M, 100 mL). The reaction solution was stirred at 25 °C for 1 hour. The reaction solution was concentrated under vacuum to give benzyl cis-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate (4 g, crude) as a yellow oil which was used for next step without further purification. Step 3: To a solution of benzyl cis-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridine-2- carboxylate (3.5 g, 12.76 mmol, 1 eq) in DMF (40 mL) was added NaH (1.5 g, 37.50 mmol, 60% purity, 2.94 eq) at 0 °C under N2. The reaction solution was stirred at 25 °C for 1 hour. MeI (2.28 g, 16.06 mmol, 1 mL, 1.26 eq) was added to the solution at 0 °C and stirred at 25 °C for another 1 hour. The mixture was quenched by H2O (100 mL), then the aqueous phase was extracted with EtOAc (100 mL, three times). The combined organic layers were dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~70% THF/Petroleum ether gradient @ 100 mL/min) to give benzyl cis-5-methyl-4-oxooctahydro- 2H-pyrrolo[3,4-c]pyridine-2-carboxylate (2.6 g, 8.66 mmol, 67.85% yield, 96% purity) as a colorless oil. MS m/z (ESI) [M+H]+= 289.1. Attorney Docket No.: 185992002240 Step 4: To a solution of benzyl cis-5-methyl-4-oxooctahydro-2H-pyrrolo[3,4- c]pyridine-2-carboxylate (2.5 g, 8.67 mmol, 1 eq) in MeOH (200 mL) was added Pd/C (300 mg, 10% purity) and Pd(OH)2 (300 mg, 20% purity) under N2. The reaction solution was degassed and purged under H2 for three times. The reaction solution was stirred at 40 °C for 3 hours. The reaction solution was filtered and the filtrate was concentrated under vacuum to give amine.7 (1.5 g, crude) as a colorless oil which was used for next step without further purification. amine.8: 3,3a,4,5,6,6a-hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide
Figure imgf000253_0001
Step 1: To a solution of dimethyl (Z)-but-2-enedioate (1 g, 6.94 mmol, 871.08 μL, 1 eq) in CH3CN (10 mL) was added N-(methoxymethyl)-1-phenyl-N- (trimethylsilylmethyl)methanamine (3.29 g, 13.88 mmol, 2 eq) at 0 °C .The mixture was stirred at 25 °C for 2 hours. The mixture was diluted with water (30mL) and extracted with EtOAc (30 mL, three times). The organic phase was washed with brine (40 mL), dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give dimethyl 1-benzylpyrrolidine-3,4-dicarboxylate (1.1 g, 3.81 mmol, 54.88% yield, 96% purity) as colorless oil. 1H NMR (400 MHz, CDCl3) d (ppm): 7.26 - 7.19 (m, 5H), 3.60 (s, 8H), 3.28 - 3.22 (m, 2H), 3.12 - 3.05 (m, 2H), 2.70 - 2.63 (m, 2H). Step 2: To a solution of dimethyl 1-benzylpyrrolidine-3,4-dicarboxylate (1 g, 3.61 mmol, 1 eq) in THF (10 mL)was added LiAlH4 (2.5 M, 5.7 mL, 3.95 eq) at 0 °C. The mixture was stirred at 60 °C for 16 hours under N2atmosphere.The reaction mixture was added Na2SO4.10 H2O (6 g) at 0 °C, and then diluted with EtOAc (20mL) filtered and concentrated under reduced pressure to give [1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl]methanol (700 Attorney Docket No.: 185992002240 mg, 3.16 mmol, 87.72% yield) as colorless oil. The crude was used next step without purification. MS m/z (ESI) [M+H]+= 222.2. Step 3: To a solution of [1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl]methanol (600 mg, 2.71 mmol, 1 eq) and TEA (1.65 g, 16.27 mmol, 2.26 mL, 6 eq) in DCM (10 mL) was added methylsulfonyl methanesulfonate (1.42 g, 8.13 mmol, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL *3). The organic phase was washed with brine (40 mL), dried over Na2SO4, filtrated and evaporated to give [1-benzyl-4-(methylsulfonyloxymethyl)pyrrolidin-3- yl]methyl methanesulfonate (1.1 g, crude) as yellow oil. The crude was used next step without purification. Step 4: To a solution of [1-benzyl-4-(methylsulfonyloxymethyl)pyrrolidin-3- yl]methyl methanesulfonate (1.1 g, 2.91 mmol, 1 eq) in DMF (11 mL) was added Na2S (682.29 mg, 8.74 mmol, 366.82 μL, 3 eq) at 25 °C. The mixture was stirred at 60 °C for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL, three times). The organic phase was washed with brine (30 mL), dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give 5-benzyl-1,3,3a,4,6,6a-hexahydrothieno[3,4-c]pyrrole (600 mg, 2.19 mmol, 75.09% yield, 80% purity) as yellow oil. 1H NMR (400 MHz, CDCl3) d (ppm): 7.35 - 7.26 (m, 5H), 3.58 (s, 2H), 3.04 - 2.84 (m, 6H), 2.60 - 2.55 (m, 2H), 2.16 - 2.15 (m, 2H). Step 5: To a solution of 5-benzyl-1,3,3a,4,6,6a-hexahydrothieno[3,4-c]pyrrole (600 mg, 2.74 mmol, 1 eq) in DCM (10 mL) was added m-CPBA (1.67 g, 8.21 mmol, 85% purity, 3 eq) at 0°C, the mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with sat.aturated Na2SO3 (50 mL) and extracted with EtOAc (60 mL, three times). The combined organic phase was washed with saturated NaCl (150 mL), dried over Na2SO4, filtrated and evaporated. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 0:1) to give 5-benzyl-1,3,3a,4,6,6a-hexahydrothieno[3,4-c]pyrrole 2,2-dioxide (370 mg, 1.47 mmol, 53.82% yield) as a white solid. 1H NMR (400 MHz, CDCl3) d (ppm): 7.36 - 7.28 (m, 5H), 3.68 (s, 2H), 3.22 ( dd, J = 7.8, 12.8 Hz, 2H), 3.06 ( d, J = 1.8 Hz, 2H), 2.98 - 2.87 (m, 4H), 2.67 ( s, 2H). Step 6: To a solution of Pd/C (37 mg, 10% purity) and Pd(OH)2 (37 mg, 20% purity) inMeOH MeOH (10 mL) was added 5-benzyl-1,3,3a,4,6,6a-hexahydrothieno[3,4-c]pyrrole 2,2-dioxide (370 mg, 1.47 mmol, 1 eq) at 25 °C under N2. The suspension was degassed Attorney Docket No.: 185992002240 under vacuum and purged with H2 three times. The mixture was stirred under H2 (50 psi) at 50°C for 16 hours. The reaction mixture was diluted with MeOH (10 mL). Then the mixture was filtered through a pad of celite and the filtrate was concentrated to give amine.8 (200 mg, crude) as a white solid. The crude was used next step without purification. MS m/z (ESI) [M+H]+= 162.2. amine.9: cis-7,7-difluoro-5-methyloctahydro-1H-pyrrolo[3,4-c]pyridine
Figure imgf000255_0001
Step 1: To a solution of tert-butyl cis-2-benzyl-7,7-difluorooctahydro-5H-pyrrolo[3,4- c]pyridine-5-carboxylate (500.00 mg, 1.42 mmol, 1 eq) in THF (10 mL) was added LAH (2.5 M, 850.00 μL, 1.5 eq) at 0 °C. The mixture was stirred at 50 °C for 16 hours under N2 atmosphere. The reaction mixture was added Na2SO4.10 H2O (750 mg) at 0 °C, and then diluted with EtOAc(20 mL) filtered and concentrated under reduced pressure to give cis-2- benzyl-7,7-difluoro-5-methyloctahydro-1H-pyrrolo[3,4-c]pyridine (440 mg, crude) was obtained as yellow oil. The crude was used next step without purification. MS m/z (ESI) [M+H]+= 267.1. Step 2: To a solution of Pd/C (44 mg, 10% purity) and Pd(OH)2 (44 mg, 20% purity) in MeOH (10 mL) was added cis-2-benzyl-7,7-difluoro-5-methyloctahydro-1H-pyrrolo[3,4- c]pyridine (440 mg, 1.65 mmol, 1 eq) at 25 °C under N2. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (50psi) at 50 °C for 16 hours. The reaction mixture was diluted with MeOH (20 mL),the mixture was filtered through a pad of celite and the filtrate was concentrated to give amine.9 (300 mg, crude) as colorless oil. The crude was used next step without purification.
Attorney Docket No.: 185992002240 amine.10: 3,3a,4,5,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrol-2-one
Figure imgf000256_0001
Step 1: To a solution of tert-butyl 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole- 5-carboxylate (2.5 g, 11.78 mmol, 1 eq) in DMF (35 mL) were added K2CO3 (4.88 g, 35.33 mmol, 3 eq) and PMB-Cl (1.94 g, 12.37 mmol, 1.68 mL, 1.05 eq) at 20°C, The mixture was stirred at 20 °C for 24 hours. The reaction mixture was diluted with water (50 ml) and then extracted with ethyl acetate(50 mL, three times). The combined organic phase was washed with brine (20 mL, three times), dried with Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~40%Ethylacetate/Petroleum ether gradient @40 mL/min) to give tert-butyl1-[(4- methoxyphenyl)methyl]-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrole-5-carboxylate (2.8 g, 8.17 mmol, 69.38% yield, 97% purity) as colorless oil. 1H NMR (400 MHz, DMSO-d6) d (ppm): 7.17 (d, J = 8.44 Hz, 2 H), 6.86 (d, J =8.44 Hz, 2 H), 3.72 (s, 3 H), 3.29 ( s, 2 H), 3.15 - 3.03 (m, 2 H), 2.97 ( t, J =6.30 Hz, 1 H), 2.83 ( s, 1 H), 2.69 ( s, 1 H), 2.21 ( d, J =7.95 Hz, 1 H), 1.91 ( d, J =9.54 Hz, 1 H), 1.50 - 1.41 (m, 1 H), 1.38 (s, 9 H). MS m/z (ESI) [M+H]+= 333.3. Step 2: To a solution of tert-butyl 1-[(4-methoxyphenyl)methyl]-2,3,3a,4,6,6a- hexahydropyrrolo [3,4-b]pyrrole-5-carboxylate (2.8 g, 8.42 mmol, 1 eq) in THF (30 mL) was added H2O (10 mL), I2 (16.03 g, 63.17 mmol, 7.5 eq) and NaHCO3 (7.08 g, 84.23 mmol, 10 eq) at 20°C, the mixture was stirred at 20 °C for12 hours. The reaction mixture was diluted with water (20mL) and then extracted with ethyl acetate(30mL, three times), the combined organic phase was washed with brine (10mL, three times) ,dried with Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50%tetrahydrofuran/Petroleum ether gradient @ 40 mL/min) to give tert-butyl1-[(4-methoxyphenyl)methyl]-2-oxo-3a,4,6,6a-tetrahydro- Attorney Docket No.: 185992002240 3H-pyrrolo [3,4-b]pyrrole-5-carboxylate (1.1 g, 2.54 mmol, 30.16% yield, 80% purity) as a yellow gum. MS m/z (ESI) [M-55]+= 291.3. Step 3: To a solution of tert-butyl1-[(4-methoxyphenyl)methyl]-2-oxo-3a,4,6,6a- tetrahydro-3H- pyrrolo[3,4-b]pyrrole-5-carboxylate (1.1 g, 3.18 mmol, 1 eq) in dioxane (2 mL) was added HCl/dioxane (2.5 M, 15 mL, 11.8 eq) at 20°C. The mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduce presser to give crude 1- [(4-methoxyphenyl) methyl]-3,3a,4,5,6,6a-hexahydropyrrolo[3,4-b]pyrrol-2-one (1 g, crude, HCl) as yellow gum which was used in the next step directly without further purification. Step 4: To a solution of 1-[(4-methoxyphenyl)methyl]-3,3a,4,5,6,6a- hexahydropyrrolo[3,4-b] pyrrol-2-one (1 g, 3.15 mmol, 1 eq, HCl) in THF (15 mL), H2O (2 mL) were added NaHCO3 (1.32 g, 15.74 mmol, 5 eq) and Cbz-Cl (800 mg, 4.69 mmol, 1.49 eq) at 20°C. The mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (30 mL, three times), the combined organic phase was washed with brine (10mL, 3 times), dried with Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~55%Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give benzyl1-[(4-methoxyphenyl)methyl]- 2-oxo-3a,4,6,6a-tetrahydro-3H- pyrrolo[3,4-b]pyrrole-5-carboxylate (1.2 g, 2.40 mmol, 76.16% yield, 76% purity) as yellow gum. MS m/z (ESI) [M+H]+= 381.1. Step 5: To a solution of benzyl1-[(4-methoxyphenyl)methyl]-2-oxo-3a,4,6,6a- tetrahydro-3H-pyrrolo [3,4-b]pyrrole-5-carboxylate (1.2 g, 2.49 mmol, 1 eq) in MeCN (20 mL), H2O (2 mL) was added ceric ammonium nitrate (6.8 g, 12.40 mmol, 6.18 mL, 4.98 eq) at 20°C. The mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with water (10 mL), quenched with saturated sodium sulfite solution (20 mL), and then extracted with ethyl acetate (30mL, three times). The combined organic phase was washed with brine (10 mL, three times), dried with Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® Silica Flash Column, Eluent of 0~80% tetrahydrofuran/Petroleum ether gradient @ 40 mL/min)to give crude product as a yellow solid. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um;mobile phase: [water(FA)-ACN]; gradient:12%-42% B over 10 min) to give benzyl 2-oxo-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrole-5-carboxylate (0.15 g, 576.29 μmol, 23.13% yield, 100% purity) as a white solid. MS m/z (ESI) [M+H]+= 261.2. Step 6: To a mixture of benzyl 2-oxo-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrole-5- carboxylate (140 mg, 537.87 μmol, 1 eq) in MeOH (20 mL) were added Pd/C (186.67 mg, Attorney Docket No.: 185992002240 175.41 μmol, 10% purity, 0.033 eq) at 20 °C. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (50psi) at 20 °C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude amine.10 as a white solid which was used in the next step directly without further purification. amine.11: 6-methyl-2,6-diazaspiro[3.5]nonan-5-one
Figure imgf000258_0001
Step 1: To a mixture of tert-butyl N-(3-hydroxypropyl)-N-methyl-carbamate (8 g, 42.27 mmol, 1 eq) and PPh3 (14.41 g, 54.95 mmol, 1.3 eq) in DCM (80 mL) was added CBr4 (18.22 g, 54.95 mmol, 1.3 eq) at 0 °C. The mixture was stirred at 0 °C for 1.5 hours under N2. The mixture was washed with water (50 ml), saturated sodium bicarbonate solution (50 ml), dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~6% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give tert-butyl N-(3-bromopropyl)-N- methyl-carbamate (8.65 g, 34.31 mmol, 81.15% yield, 100% purity) as colorless oil. 1H NMR (400 MHz, CDCl3) d (ppm): 3.44 - 3.28 (m, 4H), 2.86 (s, 3H), 2.13 - 2.01 (m, 2H), 1.45 (s, 9H). MS m/z (ESI) [M-56+H]+= 198.0. Step 2: To a mixture of O1-benzyl O3-methyl azetidine-1,3-dicarboxylate (5 g, 20.06 mmol, 1 eq) in THF (50 mL) was added LiHMDS (1 M, 26 mL, 1.3 eq) at -40 °C under N2. The mixture was stirred at -40 °C for 0.5 hour under N2, and then a solution of tert-butyl N- (3-bromopropyl)-N-methyl-carbamate (6.07 g, 24.07 mmol, 1.2 eq) in THF (10 mL) was added. The mixture was stirred at -40~10 °C for 12 hours under N2. The mixture was quenched with sat.NH4Cl solution (50 ml) at 0 °C, and then extracted with EtOAc (30 mL, 2 times). The combined organic phase was washed with brine, dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~15% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give O1-benzyl O3-methyl 3-[3-[tert- Attorney Docket No.: 185992002240 butoxycarbonyl(methyl)amino]propyl]azetidine-1,3-dicarboxylate (700 mg, 1.07 mmol, 5.35% yield, 64.5% purity) as colorless oil. 1H NMR (400 MHz, DMSO-d6) d (ppm): 7.41 - 7.29 (m, 5H), 5.03 (s, 2H), 4.19 - 4.04 (m, 2H), 3.86 - 3.60 (m, 5H), 3.13 (br t, J = 6.9 Hz, 2H), 2.74 (s, 3H), 1.83 - 1.71 (m, 2H), 1.37 (s, 11H). MS m/z (ESI) [M-11+H]+= 321.1. Step 3: A mixture of O1-benzyl O3-methyl 3-[3-[tert- butoxycarbonyl(methyl)amino]propyl]azetidine-1,3-dicarboxylate (360 mg, 856.13 μmol, 1 eq) and TFA (1.07 g, 9.42 mmol, 0.7 mL, 11.01 eq) in DCM (7 mL) was stirred at 20 °C for 1 hour, and then the mixture was adjusted to pH= 8 with saturated sodium bicarbonate solution. The mixture was stirred at 20 °C for 12 hours. The mixture (combined with another two batch) was separated, the aqueous phase was extracted with ethyl acetate (30 mL, 2 times). The combined organic phase was washed with brine, dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give benzyl 6-methyl-5-oxo-2,6-diazaspiro[3.5]nonane-2-carboxylate (550 mg, 1.91 mmol, 74.27% yield, 100% purity) as colorless oil. 1H NMR (400 MHz, DMSO-d6) d (ppm): 7.45 - 7.24 (m, 5H), 5.04 (s, 2H), 4.19 - 4.02 (m, 2H), 3.70 - 3.51 (m, 2H), 3.23 (t, J = 6.1 Hz, 2H), 2.82 (s, 3H), 2.08 - 1.98 (m, 2H), 1.77 - 1.63 (m, 2H). MS m/z (ESI) [M+H]+= 289.1. Step 4: To a mixture of Pd/C (60 mg, 56.38 μmol, 10% purity) in MeOH (10 mL) was added benzyl 6-methyl-5-oxo-2,6-diazaspiro[3.5]nonane-2-carboxylate (550 mg, 1.91 mmol, 1 eq) . The mixture was stirred at 20 °C for 12 hours under H2 (50 Psi). The mixture was filtered by celite. The filtrate was concentrated to give amine.11 (294 mg, 1.90 mmol, 99.65% yield, 99.7% purity) as colorless oil. MS m/z (ESI) [M + H]+. [M+H]+= 155.1. amine.12 & 13: 1,3-dimethyl-2thia-3,7-diazaspiro[4.4]nonane 2,2-dioxide & 3-methyl-2thia- 3,7-diazaspiro[4.4]nonane 2,2-dioxide
Figure imgf000259_0001
Step 1: To a solution of tert-butyl 3-cyanopyrrolidine-1-carboxylate (3 g, 15.29 mmol, 1 eq) in THF (30 mL) was added LDA (2 M, 15.29 mL, 2 eq) at -78 °C. The reaction mixture Attorney Docket No.: 185992002240 was stirred at -78°C for 1 hour. A solution of chloro(iodo)methane (4.04 g, 22.93 mmol, 1.66 mL, 1.5 eq) in THF (20 mL) was added dropwise into reaction mixture at -78°C. The reaction mixture was warmed up to 20 °C and stirred 1 hour at 20 °C. The reaction mixture was quenched by addition NH4Cl (50 mL) at 0 °C, and then extracted with EtOAc (50 mL, 3 times). The combined organic layers were dried over Na2SO4, filtrated and evaporated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 2/1). Compound tert-butyl 3-(chloromethyl) -3-cyano-pyrrolidine-1-carboxylate (2.5 g, 10.22 mmol, 66.83% yield) was obtained as yellow oil. 1H NMR (400 MHz, CDCl3) d (ppm): 3.95 - 3.79 (m, 1H), 3.73 - 3.47 (m, 5H), 2.48 - 2.37 (m, 1H), 2.25 - 2.12 (m, 1H), 1.48 (s, 9H). Step 2: To a solution of tert-butyl 3-(chloromethyl) -3-cyano-pyrrolidine-1- carboxylate (2.5 g, 10.22 mmol, 1 eq) in DMF (25 mL) was added acetylsulfanylpotassium (1.63 g, 14.30 mmol, 1.4 eq) at 20 °C. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was quenched by addition of water (50 mL) at 20 °C, and then extracted with EtOAc (40 mL, 3 times). The combined organic layers were dried over Na2SO4, filtrated and evaporated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 2/1). Compound tert-butyl 3-(acetylsulfanylmethyl) -3-cyano- pyrrolidine-1-carboxylate (2 g, 7.03 mmol, 68.84% yield) was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) d (ppm): 3.87 - 3.75 (m, 1H), 3.62 - 3.51 (m, 2H), 3.22 (s, 3H), 2.42 (s, 3H), 2.36 - 2.28 (m, 1H), 2.04 (s, 1H), 1.46 (s, 9H). Step 3: To a solution of tert-butyl 3-(acetylsulfanylmethyl) -3-cyano-pyrrolidine-1- carboxylate (2 g, 7.03 mmol, 1 eq) in DCM (20 mL) / Water (10 mL) was bubbled Cl2 (5.0 g, 70.52 mmol, 10.03 eq) at 0 °C for 0.5 hour. The reaction mixture was quenched by addition NaHSO3 (50 mL) at 20 °C, and then extracted with DCM (50 mL, 3 times). The combined organic layers were dried over Na2SO4, filtrated and evaporated. The crude product tert-butyl 3-(chlorosulfonylmethyl) -3-cyano-pyrrolidine-1-carboxylate (2 g, 6.48 mmol, 92.10% yield) as yellow oil was used into the next step without further purification. 1H NMR (400 MHz, CDCl3) d (ppm): 4.04 – 3.97 (m, 3H), 3.58 - 3.52 (m, 3H), 2.55 – 2.53 (m, 1H), 2.23 - 2.21 (m, 1H), 1.46 (s, 9H). Step 4: To a solution of tert-butyl 3-(chlorosulfonylmethyl) -3-cyano-pyrrolidine-1- carboxylate (2 g, 6.48 mmol, 1 eq) in MeOH (10 mL) / Water (10 mL) was added KHF2 (5.06 g, 64.77 mmol, 2.13 mL, 10 eq) at 20 °C. The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was extracted with DCM (50 mL, 3 times). The combined organic layers were dried over Na2SO4, filtrated and evaporated. The residue was purified by Attorney Docket No.: 185992002240 column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1/1). Compound tert- butyl 3-cyano-3-(fluorosulfonylmethyl) pyrrolidine-1-carboxylate (1.4 g, 4.79 mmol, 73.94% yield) was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) d (ppm): 4.09 (s, 1H), 3.87 - 3.59 (m, 4H), 3.51 (br s, 1H), 2.68 - 2.54 (m, 1H), 2.31 - 2.21 (m, 1H), 1.48 (s, 9H). Step 5: To a solution of tert-butyl 3-cyano-3-(fluorosulfonylmethyl) pyrrolidine-1- carboxylate (500 mg, 1.71 mmol, 1 eq) and NiCl2∙6H2O (447.21 mg, 1.88 mmol, 1.1 eq) in EtOH (10 mL) was cooled to -20 °C. Then NaBH4 (170 mg, 4.49 mmol, 2.63 eq) was added into the mixture at -20 °C. The reaction mixture was warmed up to 20 °C and stirred at 20 °C for 16 hours. The reaction was quenched with HCl (1 M) and the mixture was adjusted to pH 6~7. Then the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL, 3 times). The organic phase was dried over Na2SO4, filtrated and evaporated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1/1). Compound tert-butyl 2, 2-dioxo-2thia-3, 7-diazaspiro[4.4]nonane-7-carboxylate (250 mg, 904.64 μmol, 52.89% yield) was obtained as yellow oil. 1H NMR (400 MHz, CDCl3) d (ppm): 4.92 - 4.55 (m, 1H), 3.53 - 2.99 (m, 8H), 2.06 - 1.93 (m, 2H), 1.39 (s, 9H). Step 6: To a solution of tert-butyl 2, 2-dioxo-2thia-3, 7-diazaspiro[4.4]nonane-7- carboxylate (250 mg, 904.64 μmol, 1 eq) in THF (2.50 mL) was added NaH (43.42 mg, 1.09 mmol, 60% purity, 1.2 eq) at 0 °C under N2. The reaction solution was stirred at 20 °C for 30 min. Then CH3I (128.40 mg, 904.64 μmol, 56.32 μL, 1 eq) was added to the solution at 0 °C and stirred at 20 °C for another 12 h under N2. Water (10.0 mL) was added to the solution to quench the unfinished NaH. The residue was partitioned between EtOAc (20.0 mL, 2 times) and water (20.0 mL). The combined organic layers were washed by brine (20.0 mL) and dried over Na2SO4, filtrated and evaporated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1/1). Compound tert-butyl 1, 3- dimethyl-2, 2-dioxo-2thia-3, 7-diazaspiro[4.4]nonane-7-carboxylate;tert-butyl 3-methyl-2, 2- dioxo-2thia-3, 7-diazaspiro[4.4]nonane-7-carboxylate (230 mg, 386.70 μmol, 42.75% yield) was obtained as yellow oil. MS m/z (ESI) [M-56+H]+= 235.2 & MS m/z (ESI) [M-56+H]+= 249.2. Step 7: To a solution of tert-butyl 1, 3-dimethyl-2, 2-dioxo-2thia-3, 7- diazaspiro[4.4]nonane-7-carboxylate;tert-butyl 3-methyl-2, 2-dioxo-2thia-3, 7- diazaspiro[4.4]nonane-7-carboxylate (230.00 mg, 386.70 μmol, 1 eq) in EtOAc (0.50 mL) was added HCl/dioxane (2 M, 2.00 mL, 10.34 eq) at 20 °C. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the Attorney Docket No.: 185992002240 crude amine.13 (130 mg, 329.49 μmol, 85.21% yield) as brown oil used into the next step without further purification. amine.14: 1-(pyrrolidin-3-ylmethyl)pyrrolidine
Figure imgf000262_0001
Step 1: To a solution of tert-butyl 3-formylpyrrolidine-1-carboxylate (1 g, 5.02 mmol, 1 eq) in dioxane MeOH (10 mL) was added pyrrolidine (400 mg, 5.62 mmol, 469.48 μL, 1.12 eq) , AcOH (1.05 g, 17.47 mmol, 1 mL, 3.48 eq) and NaBH3CN (1 g, 15.91 mmol, 3.17 eq). Then the resulting mixture was purged with N2 three timesand stirred at 25°C for 12 hours. The reaction mixture was partitioned between EtOAc (150 mL) and water (80 mL), washed with brine (70 mL), died over Na2SO4, filtrated and evaporated. The crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give tert-butyl 3- (pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxylate (450 mg, 1.77 mmol, 35.25% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) d (ppm): 3.92 - 3.64 (m, 4H), 3.39 - 3.30 (m, 2H), 3.23 - 3.14 (m, 2H), 3.08 (br dd, J = 8.4, 10.8 Hz, 1H), 2.66 - 2.56 (m, 1H), 2.26 - 2.14 (m, 5H), 1.86 - 1.65 (m, 2H), 1.46 (s, 9H). Step 2: To a solution of tert-butyl 3-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxylate (450 mg, 1.77 mmol, 1 eq) in DCM (4 mL) was added TFA (3.07 g, 26.92 mmol, 2 mL, 15.22 eq) , then the resulting mixture was stirred at 25°C for 1 hours. The reaction mixture was evaporated under reduced pressure. The amine.14 was obtained (250 mg, crude) as the colorless oil was used without further purification. MS m/z (ESI) [M+H]+= 155.3. amine.15: 3-methyl-1,7-diazaspiro[4.4]nonan-2-one
Figure imgf000262_0002
Step 1: To a solution of tert-butyl 3-nitropyrrolidine-1-carboxylate (1 g, 4.62 mmol, 1 eq) and methyl 2-methylprop-2-enoate (509.30 mg, 5.09 mmol, 1.1 eq) in THF (10 mL) was added TBAF (1 M, 9.25 mL, 2 eq) at 25 °C . The mixture was stirred at 70 °C for 16 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL, 3 times). The Attorney Docket No.: 185992002240 organic phase was washed with brine (40 mL), dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® Silica Flash Column, Eluent of 0~50% EtOAc/PE gradient @ 40 mL/min) to give tert-butyl 3-(3- methoxy-2-methyl-3-oxo-propyl)-3-nitro-pyrrolidine-1-carboxylate (580 mg, 1.83 mmol, 39.64% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) d (ppm): 4.38 - 4.19 (m, 1H), 3.70 (s, 3H), 3.62 - 3.27 (m, 3H), 2.84 - 2.68 (m, 1H), 2.59 - 2.40 (m, 2H), 2.22 - 1.96 (m, 2H), 1.50 - 1.42 (m, 9H), 1.23 - 1.18 (m, 3H). Step 2: To a solution of Pd/C (58 mg, 10% purity) in MeOH (10 mL)/THF (10 mL) was added tert-butyl 3-(3-methoxy-2-methyl-3-oxo-propyl)-3-nitro-pyrrolidine-1-carboxylate (580 mg, 1.83 mmol, 1 eq) under N2. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (1 Mpa) at 40°C for 16 hours. The reaction mixture was diluted with MeOH (10 mL) then mixture was filtered through a pad of celite and the filtrate was concentrated to give residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~50% EtOAc/PE gradient @ 40 mL/min) to give tert-butyl 3-methyl-2-oxo-1,7- diazaspiro[4.4]nonane-7-carboxylate (180 mg, 707.76 μmol, 38.60% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) d (ppm): 3.51 - 3.28 (m, 3H), 2.67-2.57 (m, 1H), 2.46 - 2.29 (m, 1H), 2.04 - 1.84 (m, 2H), 1.72 - 1.59 (m, 2H), 1.47 (s, 8H), 1.24 (d, J = 7.2 Hz, 3H). Step 3: To a solution of tert-butyl 3-methyl-2-oxo-1,7-diazaspiro[4.4]nonane-7- carboxylate (180 mg, 707.76 μmol, 1 eq) in DCM (1 mL) was added TFA (307.00 mg, 2.69 mmol, 0.2 mL, 3.80 eq) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure to give amine 15 (120 mg, crude) as a yellow solid. The crude was used next step without purification. amine.16: hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one
Figure imgf000263_0001
Step 1: To a solution of tert-butyl 5-oxo-2H-pyrrole-1-carboxylate (2 g, 10.92 mmol, 1 eq) in MeCN (25 mL) was added N-(methoxymethyl)-1-phenyl-N- (trimethylsilylmethyl)methanamine (3.9 g, 16.43 mmol, 1.5 eq). The mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by reversed-phase HPLC (0.1% FA Attorney Docket No.: 185992002240 condition) and lyophilized to give the tert-butyl 5-benzyl-1-oxohexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (1.2 g, 3.79 mmol, 34.74% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) d (ppm): 7.35 - 7.28 (m, 5H), 3.90 (d, J = 8.7, 11.2 Hz, 1H), 3.83 - 3.74 (m, 1H), 3.72 - 3.63 (m, 1H), 3.54 (d, J = 3.0, 11.3 Hz, 1H), 3.28 - 3.11 (m, 2H), 2.92 - 2.78 (m, 3H), 2.72 - 2.64 (m, 1H), 1.54 (s, 9H). Step 2: To a solution of tert-butyl 5-benzyl-1-oxohexahydropyrrolo[3,4-c]pyrrole- 2(1H)-carboxylate (600 mg, 1.90 mmol, 1 eq) in DCM (5 mL) was added TFA (3.07 g, 26.92 mmol, 2 mL, 14.20 eq), then the resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was evaporated under reduced pressure to give the crude product. The 5- benzylhexahydropyrrolo[3,4-c]pyrrol-1(2H)-one (600 mg, crude) as the yellow oil was used without further purification. MS m/z (ESI) [M+H]+= 217.3. Step 3: 5-benzylhexahydropyrrolo[3,4-c]pyrrol-1(2H)-one (600 mg, 2.77 mmol, 1 eq) in MeOH (50 mL), The fixed bed (FLR1, volume 5 mL) was completely packed with granular catalyst 5%Pd(OH)2/Al2O3 (1.00 eq). The H2 back pressure regulator was adjusted to 1.5 MPa, and the flow rate of H2 was 20 mL/min. Then the solution S1 was pumped by Pump 1 {S1, P1, 0.4 mL/min } to fixed bed {FLR1,SS,Fixed bed,6.350(1/4’’) mm, 1 mL, 45°C }. Then the reaction mixture was collected from the reactor output. The fixed bed was washed by extra {MeOH,50 mL}. The fixed bed was evaporated under reduced pressure to give amine 16 (400 mg, crude) as a white solid. amine.17: (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-2(1H)-one
Figure imgf000264_0001
Step 1: To a solution of tert-butyl (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrole-5(1H)- carboxylate (1.00 g, 4.71 mmol, 1.00 eq), 4-methoxybenzaldehyde (830 mg, 6.10 mmol, 1.29 eq) in MeOH (20.0 mL) were added acetic acid (141 mg, 2.36 mmol, 0.500 eq) and sodium cyanoborohydride (590 mg, 9.39 mmol, 1.99 eq) at 0°C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (30.0 mL) and then extracted with Attorney Docket No.: 185992002240 EtOAc (30.0 mL, 3 times). The combined organic phase was washed with brine (10.0 mL, 3 times), dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20% THF/PE gradient @ 40 mL/min) to give tert-butyl (3aS,6aS)-1-(4- methoxybenzyl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (1.00 g, 2.91 mmol, 61.9% yield, 96.9% purity) as colorless oil. MS m/z (ESI) [M+H]+= 333.3. Step 2: To a solution of tert-butyl (3aS,6aS)-1-(4- methoxybenzyl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (1.00 g, 96.9% purity, 3.01 mmol, 1.00 eq) in THF (35.0 mL) were added H2O (15.0 mL), I2 (4.50 g, 17.7 mmol, 5.89 eq) and NaHCO3 (2.55 g, 30.35 mmol, 10.1 eq) at 25°C. The mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was diluted with water (50.0 mL), quenched with sodium sulfite (20.0 g), extracted with EtOAc (50.0 mL, 3 times), the combined organic phase was washed with brine (20.0 mL, 3 times), dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~28% EtOAc/PE gradient @ 40 mL/min) to give tert-butyl (3aS,6aS)-1-(4-methoxybenzyl)-2-oxohexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (700 mg, 1.79 mmol, 59.7% yield, 88.8% purity) as a yellow gum. MS m/z (ESI) [M-55]+= 291.1. Step 3: To a solution of tert-butyl (3aS,6aS)-1-(4-methoxybenzyl)-2- oxohexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (700 mg, 1.80 mmol, 1.00 eq) in dioxane (5.00 mL) was added HCl / dioxane (2.00 M, 15.0 mL) at 25°C. The mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated under reduce presser to give crude (3aS,6aS)-1-(4-methoxybenzyl)hexahydropyrrolo[3,4-b]pyrrol-2(1H)-one (550 mg, crude, HCl) as yellow gum which was used in the next step directly without further purification. Step 4: To a solution of (3aS,6aS)-1-(4-methoxybenzyl)hexahydropyrrolo[3,4- b]pyrrol-2(1H)-one (crude 550 mg, 1.95 mmol, 1.00 eq, HCl) in THF (10.0 mL), H2O (2.00 mL) were added NaHCO3 (1.50 g, 17.86 mmol, 9.18 eq) and benzyl carbonochloridate (600 mg, 3.52 mmol, 1.81 eq) at 25°C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (20.0 mL) and then extracted with EtOAc (30.0 mL, 3 times), the combined organic phase was washed with brine (10.0 mL, 3 times), dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% THF/PE gradient @ 40 mL/min) to give benzyl (3aS,6aS)-1-(4-methoxybenzyl)-2-oxohexahydropyrrolo[3,4- Attorney Docket No.: 185992002240 b]pyrrole-5(1H)-carboxylate (550 mg, 1.43 mmol, 72.8% yield, 98.5% purity) as yellow gum. MS m/z (ESI) [M+H]+= 381.3. Step 5: To a solution of benzyl (3aS,6aS)-1-(4-methoxybenzyl)-2- oxohexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (550 mg, 98.5% purity, 1.43 mmol, 1.00 eq) in MeCN (10 mL), H2O (4.00 mL) was added ceric ammonium nitrate (1.71 g, 3.12 mmol, 2.20 eq) at 25℃. The mixture was stirred at 25℃ for 0.5 hour. The reaction mixture was diluted with water (50.0 mL), quenched with sodium sulfite (20.0 g). extracted with EtOAc (30. 0ml), the combined organic phase was washed with brine (10.0 mL), dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, Eluent of 0~50% THF/PE gradient @ 40 mL/min) to give crude product as yellow gum, the crude product was then purified by prep- TLC (SiO2: ethyl acetate : methanol= 10:1) to give benzyl (3aS,6aS)-2- oxohexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (120 mg, 374 μmol, 26.4% yield, 81.5% purity) as yellow gum. MS m/z (ESI) [M+H]+= 521.3. Step 6: To a solution of benzyl (3aS,6aS)-2-oxohexahydropyrrolo[3,4-b]pyrrole- 5(1H)-carboxylate (120 mg, 81.5% purity, 374 μmol, 1.00 eq) in MeOH (10.0 mL) was added Pd/C (100 mg, 94.0 μmol, 10.0 % purity, 2.52e-1 eq) at 25°C. The mixture was stirred at 25°C for 2 hours under H2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude amine 17 (50.0 mg, crude) as yellow gum which was used in the next step directly without further purification. Synthesis of substituted dichloroquinoline intermediates A.4 A.4a (R7 = -H; R8 = -F; R9 = -OCH3; R10 = -H): 2, 4-dichloro-7-fluoro-6-methoxy- quinoline
Figure imgf000266_0001
According to Scheme 1 Step 3: To a solution of 3-fluoro-4-methoxy-aniline A.3a (2.0 g, 14 mmol, 1.0 eq) and malonic acid (1.6 g, 15 mmol, 1.6 mL, 1.1 eq) in POCl3 (33 g, 215 mmol, 20 mL, 15 eq) at 25 °C. The mixture was stirred at 25 °C for 3 h, then stirred at 90 °C for 12 h. The reaction mixture was added into H2O and held the temperature at 20 °C ~ 30 °C, washed with aq. NaHCO3 then was partitioned between ethyl acetate (30 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (30 mL) twice. The combined organic layers were dried over Na2SO4 and evaporated to give a crude material. The residue Attorney Docket No.: 185992002240 obtained was purified by Flash chromatography (40 g column, Eluent of 0~10% EtOAc/PE gradient at 40 mL/min) to afford A.4a (1.9 g, 7.7 mmol, 54% yield, 100% purity) as white solid. 1H NMR (400 MHz, DMSO-d6) d (ppm): 7.89 (m, 2H), 7.59 (d, J = 8.9 Hz, 1H), 4.06 (s, 3H). MS m/z (ESI) [M+H]+ = 246.0. A.4b R9 = -NHCH2CH2O-; R7,10 = -H): 7,9-dichloro-3,4-dihydro-2H-pyrido[2,3-g] [1,4] benzoxazine
Figure imgf000267_0001
According to Scheme 1 Step 1: To a solution of 6-nitro-3,4-dihydro-2H-1,4- benzoxazine A.1b (4.2 g, 23 mmol, 1.0 eq) and NaOH (2.8 g, 70 mmol, 1.3 mL, 3.0 eq) in THF (40 mL) was added Fmoc-Cl (7.2 g, 28 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL, three times). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue obtained was purified by Flash chromatography (120 g column, Eluent of 0~100% EtOAc/PE gradient at 50 mL/min) to give 9H-fluoren-9-ylmethyl 6-nitro-2,3- dihydro-1,4-benzoxazine-4-carboxylate A.2b (7.6 g, 17 mmol, 71% yield, 88% purity) as a yellow solid. MS m/z (ESI) [M+Na]+ = 425.1. According to Scheme 1 Step 2: To a solution of A.2b (7.6 g, 19 mmol, 1.0 eq) and NH4Cl (6.1 g, 113 mmol, 6.0 eq) in EtOH (60 mL) / H2O (60 mL) was added Fe (5.3 g, 94 mmol, 5.0 eq) at 60 °C, the mixture was stirred at 60 °C for 16 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL, three times). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue obtained was purified by Flash chromatography (Eluent of 0~100% EtOAc/PE gradient at 50 mL/min) to give 9H-fluoren-9- ylmethyl 6-amino-2,3-dihydro-1,4-benzoxazine-4-carboxylate A.3b (6.0 g, 13 mmol, 68% yield, 80% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 373.2. According to Scheme 1 Step 3: A mixture of A.3b (5.0 g, 13 mmol, 1.0 eq) and malonic acid (1.6 g, 15 mmol, 1.6 mL, 1.1 eq) in POCl3 (50 mL) was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove POCl3, the reaction mixture was quenched with water (200 mL) at 25 °C, the mixture was adjusted to pH = 7~8 with NaHCO3.The mixture was diluted with water (200 mL) and extracted with ethyl Attorney Docket No.: 185992002240 acetate (200 mL, three times). The combined organic phases were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. The mixture was concentrated to give a residue. The residue obtained was purified by Flash chromatography (25 g column, Eluent of 0~100% EtOAc/PE gradient at 50 mL/min) to give 9H-fluoren-9-ylmethyl 7,9-dichloro-2,3-dihydropyrido[2,3-g] [1,4] benzoxazine-4-carboxylate A.4b’ (1.0 g, 1.3 mmol, 9.8% yield, 63% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 477.1. Intermediate A.4b’ underwent an additional step of deprotection. To a solution of A.4b’ (0.90 g, 1.9 mmol, 1.0 eq) in DCM (5.0 mL) was added diethylamine (3.2 g, 44 mmol, 4.5 mL, 23 eq) at 25 °C. The mixture was stirred at 60 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL, three times). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue obtained was purified by Flash chromatography (20 g column, Eluent of 0~50% EtOAc/PE gradient at 40 mL/min) to give A.4b (0.15 g, 0.59 mmol, 31% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6) d (ppm): 7.45 (s, 1H), 7.29 (s, 1H), 7.24 (s, 1H), 4.33 - 4.29 (m, 2H), 3.59 - 3.54 (m, 2H). A.4c (R8 = -O-pyridine; R7,9,10 = -H): 2,4-dichloro-7-(3-pyridyloxy) quinoline According to Scheme 1 Step 1: To a mixture of 1-fluoro-3-nitrobenzene A.1c (10 g, 71 mmol, 7.6 mL, 1.0 eq) and pyridin-3-ol (8.1 g, 85 mmol, 1.2 eq) in DMF (100 mL) was added potassium carbonate (20 g, 0.14 mol, 2.0 eq) at 20 °C. The reaction mixture was stirred at 130 °C for 48 h. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (500 mL, twice). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (SiO2, PE/EtOAc = 10:1 to 3:1) to give 3-(3-nitrophenoxy) pyridine A.2.c (7.0 g, 45% yield) as a yellow oil. MS m/z (ESI) [M+H] + = 216.9. According to Scheme 1 Step 2: To a mixture of A.2c (7.0 g, 32 mmol, 1.0 eq) in a mixed solution of ethanol (80 mL) and water (10 mL) was added ammonium chloride (14 g, 0.26 mol, 8.0 eq) at 20 °C. The reaction mixture was stirred at 80 °C and Fe (9.0 g, 0.16 mol, 5.0 eq) was added to the reaction mixture in batches at 80 °C. Then the reaction mixture was Attorney Docket No.: 185992002240 stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (SiO2, PE/EtOAc = 5:1 to 1:1) to give 3-(3-pyridyloxy) aniline A.3c (4.0 g, 66% yield) as yellow oil. According to Scheme 1 Step 3: A mixture of A.3c (4.0 g, 22 mmol, 1.0 eq) and malonic acid (2.5 g, 24 mmol, 2.5 mL, 1.1 eq) in phosphorus oxychloride (40 mL) as stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature and most of the phosphorus oxychloride was removed by decompress distillation to give a residue. The residue was quenched with saturated sodium hydrogen carbonate solution (500 mL) and extracted with ethyl acetate (500 mL, twice). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (SiO2, PE/EtOAc = 10:1 to 3:1) and prep-TLC (SiO2, PE/EtOAc = 3:1) to afford A.4c (0.20 g, 3% yield) as a yellow solid. MS m/z (ESI) [M+H]+ = 290.9. A.4d (R8 = -N 2; R7,9,10 = -H): 2,4-dichloro-N, N-dimethyl-quinolin-7-amine
Figure imgf000269_0001
Figure imgf000269_0002
According to Scheme 1 Step 3: To a solution of N1, N1-dimethylbenzene-1,3-diamine A.3d (10 g, 73 mmol, 1.0 eq) in phosphorus oxychloride (90 mL) was added malonic acid (10 g, 96 mmol, 10 mL, 1.3 eq) at 25 °C. After stirring at 110 °C for 16 h, the reaction mixture was added into saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate 300 mL (3 x 100 mL). The combined organic layers were washed with brine 300 mL (3 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (80 g column, Eluent of 0~7% EtOAc/PE gradient at 30 mL/min) to give A.4d (1.5 g, 5.9 mmol, 8.1% yield, 95% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 241.0. A.4e (R8 = -NHCH3; R9 = -OCH3; R7,10 = -H): 2,4-dichloro-6-methoxy-N-methyl-quinolin- 7-amine
Figure imgf000269_0003
Attorney Docket No.: 185992002240 According to Scheme 1 Step 1: To a solution of N-(3-amino-4-methoxy-phenyl) acetamide A.1e (12 g, 67 mmol, 1.0 eq) in methyl alcohol (100 mL) / acetic acid (10 mL) was added formaldehyde (2.0 g, 67 mmol, 1.8 mL, 1.0 eq) and sodium cyanoborohydride (13 g, 0.20 mol, 3.0 eq) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was added into water (200 mL) and adjusted the pH = 7-8 and then extracted with ethyl acetate 300 mL (3 x 100 mL). The combined organic layers were washed with brine 300 mL (3 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (80 g column, Eluent of 0~50% EtOAc/PE gradient at 60 mL/min) to give N-[4-methoxy-3-(methylamino) phenyl] acetamide A.2e’ (7.0 g, 24 mmol, 36% yield, 66% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 195.0. Intermediate A.2e’ underwent an additional step of protection. To a solution of A.2e’ (6.5 g, 22 mmol, 1.0 eq) in dioxane (100 mL) was added sodium bicarbonate (5.6 g, 66 mmol, 2.6 mL, 3.0 eq) and 9H-fluoren-9-ylmethyl carbonochloridate (6.3 g, 24 mmol, 1.1 eq) at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was added into water (100 mL) and extracted with ethyl acetate 120 mL (3 x 40 mL). The combined organic layers were washed with brine 120 mL (3 x 40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (80 g column, Eluent of 0~50% EtOAc/PE gradient at 60 mL/min) to give 9H-fluoren-9-ylmethyl N-(5- acetamido-2-methoxy-phenyl)-N-methylcarbamate A.2e (10 g, 19 mmol, 87% yield, 80% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 417.2. According to Scheme 1 Step 2: To a solution of A.2e (9.9 g, 24 mmol, 1.0 eq) in MeOH (100 mL) was added sulfuric acid (12 M, 20 mL, 10 eq) at 25 °C. After stirring at 60 °C for 16 h, the reaction mixture was added into water and adjusted the pH to 7-8, extracted with ethyl acetate 120 mL (3 x 40 mL). The combined organic layers were washed with brine 120 mL (3 x 40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 9H-fluoren-9-ylmethyl N-(5-amino-2-methoxy-phenyl)-N-methylcarbamate A.3e (11 g, 24 mmol, 99% yield, 80% purity) as a yellow gum. MS m/z (ESI) [M+H]+ = 375.1. According to Scheme 1 Step 3: To a solution of A.3e (10 g, 27 mmol, 1.0 eq) in phosphorus oxychloride (90 mL) was added malonic acid (3.5 g, 34 mmol, 3.5 mL, 1.3 eq) at 25 °C. After stirring at 110°C for 16 h, the reaction mixture was concentrated under reduced pressure. The residue was added into saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate 300 mL (3 x 100 mL). The combined organic layers were washed with water (100 mL) and brine 300 mL (3 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by Flash Attorney Docket No.: 185992002240 chromatography (40 g column, Eluent of 0~20% EtOAc/PE gradient at 60 mL/min) to give 9H-fluoren-9-ylmethyl N-(2,4-dichloro-6-methoxy-7-quinolyl)-N-methylcarbamate A.4e’ (2.0 g, 3.3 mmol, 12% yield, 78% purity) as a yellow solid. MS m/z (ESI) [M+H] + = 479.1. Intermediate A.4e’ underwent an additional step of deprotection. To a solution of A.4e’ (2.0 g, 4.2 mmol, 1.0 eq) in dichloromethane (20 mL) was added piperidine (8.6 g, 0.10 mol, 10 mL, 24 eq) at 25 °C. After stirring at 60 °C for 2 h, the reaction mixture was added into water and extracted with ethyl acetate 60 mL (3 x 20 mL). The combined organic layers were washed with brine 60 mL (3 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (12 g column, Eluent of 0~30% EtOAc/PE gradient at 45 mL/min) to give A.4e (0.60 g, 1.6 mmol, 39% yield, 70% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 256.9. A.4f (R8 = -OCF3; R7,9,10 = -H): 2,4-dichloro-7-(trifluoromethoxy) quinoline
Figure imgf000271_0001
According to Scheme 1 Step 3: To a solution of 3-(trifluoromethoxy) aniline A.3f (10 g, 56 mmol, 7.6 mL, 1.0 eq) in POCl3 (90 mL) was added malonic acid (7.5 g, 72 mmol, 7.5 mL, 1.3 eq) at 20 °C. The reaction mixture was stirred at 20 °C for 2 h, then the reaction mixture was stirred at 110 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with saturated aqueous NaHCO3 (500 mL). The mixture was then extracted with ethyl acetate (1000 mL, three times). The combined organic phases were washed with brine (1000 mL, three times), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (80g column, Eluent of 0~10% EtOAc/PE gradient at 40 mL/min) to afford A.4f (5.2 g, 18 mmol, 33% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) d (ppm): 8.28 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 0.7 Hz, 1H), 7.59 - 7.50 (m, 2H). A.4g (R8 = -F; R9 = -CH3; R7,10 = -H): 2,4-dichloro-6-fluoro-N, N-dimethyl-quinolin-7-amine
Figure imgf000271_0002
According to Scheme 1 Step 1: To a solution of 2-fluoro-5-nitro-aniline A.1g (10 g, 64 mmol, 1.0 eq) in MeOH (100 mL) /AcOH (10 mL) was added HCHO (5.8 g, 192 mmol, Attorney Docket No.: 185992002240 5.3 mL, 3.0 eq) at 25 °C. After stirring at 25 °C for 48 h. The reaction mixture was added into saturated aqueous solution of ammonium chloride (200 mL) and extracted with ethyl acetate 300 mL (100 mL, three times). The combined organic layers were washed with brine 300 mL (100 mL, three times), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (40 g column, Eluent of 0~5% EtOAc/PE gradient at 45mL/min) to give 2-fluoro-N, N-dimethyl-5-nitro-aniline A.2g (7.0 g, 36 mmol, 56% yield, 95% purity) as yellow oil. MS m/z (ESI) [M+H]+ = 185.1. According to Scheme 1 Step 2: To a solution of Pd/C (0.10 g, 10% purity) in ethyl acetate (20 mL) was added A.2g (1.0 g, 5.4 mmol, 1.0 eq) under N2 atmosphere at 25 °C. The suspension was degassed and purged with H2 three times at 25 °C. After stirring under H2 (15 Psi) at 25 °C for 16 h, the reaction mixture was filtered and concentrated under reduced pressure to give 4-fluoro-N3, N3-dimethyl-benzene-1,3-diamine A.3g (0.70 g, 4.1 mmol, 75% yield, 90% purity) as brown oil. MS m/z (ESI) [M+H]+ = 155.1. According to Scheme 1 Step 3: To a solution of A.3g (0.70 g, 4.5 mmol, 1.0 eq), malonic acid (0.5 g, 4.8 mmol, 0.50 mL, 1.1 eq) in POCl3 (7.0 mL) at 25 °C. After stirring at 100 °C for 16 h, the reaction mixture was added into saturated sodium bicarbonate aqueous solution (100 mL) and extracted with ethyl acetate 60 mL (20 mL, three times). The combined organic layers were washed with brine 60 mL (20 mL, three times), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (40 g column, Eluent of 0~5% EtOAc/PE gradient at 45 mL/min) to give A.4g (0.17 g, 0.59 mmol, 13% yield, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 259.1. A.4h (R8 = -Br; R7,9,10 = -H): 7-bromo-2,4-dichloro-quinoline
Figure imgf000272_0001
According to Scheme 1 Step 3: To a solution of 3-bromoaniline A.3h (10 g, 58 mmol, 6.3 mL, 1 eq) and malonic acid (6.7 g, 64 mmol, 6.7 mL, 1.1 eq) in POCl3 (100 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h. Then the mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove POCl3. The reaction mixture was quenched with water (200 mL) at 25 °C, the mixture was adjusted to pH=7~8 with NaHCO3.The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL, three times). The combined organic phases were washed with brine (600 mL), dried Attorney Docket No.: 185992002240 over anhydrous Na2SO4, filtered and the filtrate was concentrated. The residue obtained was purified by column chromatography (SiO2, PE/EtOAc). A.4h (3.0 g, 11 mmol, 19% yield, 100% purity) was obtained as a white solid. MS m/z (ESI) [M+H]+ = 277.9. A.4i (R8,9 = -F; R7,10 = -H): 2, 4-dichloro-6, 7-difluoro-quinoline
Figure imgf000273_0001
According to Scheme 1 Step 3: To a solution of malonic acid (9.0 g, 86 mmol, 9.0 mL, 1.1 eq) in POCl3 (80 mL) was added 3, 4-difluoroaniline A.3i (10 g, 77 mmol, 1.0 eq) at 25 °C. The mixture was stirred at 110 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with ethyl acetate (0.10 L). The pH of the mixture was adjusted with sodium bicarbonate solution (2.0 M). The mixture was extracted with EtOAc (0.10 L, twice). The combined organic layers were washed with saturated salt solution (0.10 L, twice), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, PE/EtOAc = 10:1 to 5:1) to give A.4i (3.0 g, 12 mmol, 15% yield, 90% purity) as a yellow solid. A.4j (R8 = -OCD3; R7,9,10 = -H): 2,4-dichloro-7-(trideuteriomethoxy) quinoline
Figure imgf000273_0002
Step 1: To a solution of 2,4-dichloro-7-methoxy-quinoline (1.0 g, 4.4 mmol, 1.0 eq) in DCM (15 mL) was added boron tribromide (2.6 g, 10 mmol, 2.4 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by methanol (20 mL), the mixture was diluted with water (50 mL) and then to the mixture was added sodium bicarbonate until the pH = 7. The above mixture was then extracted with DCM (50 mL, three times), washed with brine (20 mL, three times), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (20 g column, Eluent of 0~30% EtOAc/PE gradient at 40 mL/min) to give 2,4-dichloroquinolin-7-ol (0.85 g, 3.7 mmol, 84% yield, 93% purity) as a white solid. MS m/z (ESI) [M+H]+ = 214.1. Step 2: To a solution of 2,4-dichloroquinolin-7-ol (0.40 g, 1.9 mmol, 1.0 eq) in ACN (8.0 mL) was added potassium carbonate (0.52 g, 3.7 mmol, 2.0 eq) and Attorney Docket No.: 185992002240 trideuterio(iodo)methane (0.35 g, 2.4 mmol, 1.3 eq) at 20 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (12 g column, Eluent of 0~20% EtOAc/PE gradient at 30 mL/min) to give A.4j (0.30 g, 1.3 mmol, 70% yield, 100% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) d (ppm): 8.11 - 8.03 (m, 1H), 7.73 (s, 1H), 7.46 - 7.37 (m, 2H). MS m/z (ESI) [M+H]+ = 231.2. A.4k (R8 = -OCD3; R9 = -F; R7,10 = -H): 4 - 2,4-dichloro-6-fluoro-7- (trideuteriomethoxy)quinoline
Figure imgf000274_0001
Step 1: To a solution of 4-fluoro-3-methoxy-aniline (10 g, 70.85 mmol, 1 eq) in POCl3 (164.50 g, 1.07 mol, 100 mL, 15.14 eq) was added malonic acid (7.4 g, 71.11 mmol, 7.40 mL, 1 eq), the reaction mixture was stirred at 110 °C for 12 hours. TLC (PE:EA=5:1, Rf=0.53) showed one major spot was detected. The reaction solution was quenched by H2O (100 mL). The pH of the residue was adjusted to 8 by adding sat. NaHCO3. The residue was extracted by EtOAc (300 mL, 2 times), The organic phase was washed by sat. NaHCO3 (200 mL, 3 times). The combined organic layers were dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to afford 2, 4-dichloro-6-fluoro-7-methoxy-quinoline (15 g, 60.17 mmol, 84.92% yield, 98.7% purity) as a light green solid. MS m/z (ESI) [M+H]+.= 246.0. 1H NMR (400 MHz, CDCl3) d (ppm): 4.04 (s, 3 H) 7.43 (s, 1 H) 7.47 (d, J=7.95 Hz, 1 H) 7.81 (d, J=11.37 Hz, 1 H) . Step 2: To a soluton of 2, 4-dichloro-6-fluoro-7-methoxy-quinoline (10 g, 40.64 mmol, 1 eq) in DCM (100 mL) was added BBr3 (2 M, 42 mL, 2.07 eq) at 0 °C. The mixture was stirred at 0°C for 2 hours. TLC (PE/EtOAc=3/1, Rf=0.32) showed one major spot was observed. The reaction mixture was quenched with methanol (100 mL), the mixture was diluted with water (200mL) and then treated with sodium bicarbonate to attend pH=7. The mixture was extracted with ethyl acetate (100mL, 3 times), the combined organic phase was washed with brine (2100mL, 2 times), dried with anhydrous Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®;80 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ Attorney Docket No.: 185992002240 100 mL/min) to afford 2, 4-dichloro-6-fluoro-quinolin-7-ol (9.4 g, 40.51 mmol, 99.68% yield, 100% purity) as white solid. MS m/z (ESI) [M+H]+ = 232.0. Step 3: To a solution of 2, 4-dichloro-6-fluoro-quinolin-7-ol (9.4 g, 40.51 mmol, 1 eq) in DMF (100 mL) was added trideuterio (iodo) methane (7.2 g, 49.67 mmol, 3.09 mL, 1.23 eq) and K2CO3 (17 g, 123.00 mmol, 3.04 eq), the reaction mixture was stirred at 25 °C for 12 hours. TLC (PE/EtOAc=5/1, Rf=0.32) showed one major spot was observed. The reaction mixture was filtered and the filtrate was poured into water (1000 mL), extracted with EtOAc (500 mL, 3 times). The combined organic phase was washed with saturated brine (500 mL, 2 times), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to afford A.4k (6.4 g, 25.69 mmol, 63.43% yield, 100% purity) as white solid. MS m/z (ESI) [M+H]+= 249.1. 1H NMR (400 MHz, CD3OD) d (ppm): 7.59 (br d, J=7.34 Hz, 1 H) 7.70 (br s, 1 H) 7.97 (br d, J=10.39 Hz, 1 H). A.4l (R8 = - -H): 2,4-dichloro-6-fluoro-N,N-dimethylquinolin-7-
Figure imgf000275_0001
amine
Figure imgf000275_0002
Step 1: To a solution of 2-fluoro-5-nitro-aniline (10 g, 64.06 mmol, 1 eq) in MeOH (100 mL)/AcOH (10 mL) was added HCHO (5.77 g, 192.17 mmol, 5.29 mL, 3 eq) at 25°C. After stirring at 25 °C for 48 hours the reaction mixture was added into saturated aqueous solution of ammonium chloride (200 mL) and extracted with ethyl acetate (100 mL, 3 times). The combined organic layers were washed with brine (100 mL, 3 times), dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethylacetate/Petroleum ether gradient @ 45mL/min) to give 2-fluoro-N,N-dimethyl-5-nitro-aniline (7 g, 36.11 mmol, 56.37% yield, 95% purity) as yellow oil. MS m/z (ESI) [M+H]+ = 185.1. Step 2: To a solution of Pd/C (0.1 g, 10% purity) in ethyl acetate (20 mL) was added 2-fluoro-N,N-dimethyl-5-nitro-aniline (1 g, 5.43 mmol, 1 eq) under N2 atmosphere at 25°C. The suspension was degassed and purged with H23 times at 25°C. After stirring under H2 (15 Psi) at 25 °C for 16 hours, the reaction mixture was filtered and concentrated under reduced Attorney Docket No.: 185992002240 pressure to give 4-fluoro-N3,N3-dimethyl-benzene-1,3-diamine (0.7 g, 4.09 mmol, 75.25% yield, 90% purity) as brown oil. MS m/z (ESI) [M+H]+ = 155.1. Step 3: To a solution of 6-fluoro-N1,N1-dimethylbenzene-1,3-diamine (0.7 g, 4.54 mmol, 1 eq), malonic acid (0.5 g, 4.80 mmol, 500.00 μL, 1.06 eq) in POCl3 (7 mL) at 25°C. After stirring at 100°C for 16 hours, the reaction mixture was added into saturated sodium bicarbonate aqueous solution (100 mL) and extracted with ethyl acetate 60 mL (20 mL, 3 times). The combined organic layers were washed with brine 60 mL (20 mL , 3 times), dried over Na2SO4, filtrated and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethylacetate/Petroleum ether gradient @ 45 mL/min) to give A.4l (0.17 g, 590.49 μmol, 13.01% yield, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 259.1. A.4m: 5-[(2,4-dichloro-6-fluoro-7-quinolyl)oxy]pent-1-ynyl-trimethyl-silane
Figure imgf000276_0001
To a solution of 2,4-dichloro-6-fluoro-quinolin-7-ol (400 mg, 1.72 mmol, 1 eq) in DCM (2 mL) was added 5-trimethylsilylpent-4-yn-1-ol (400 mg, 2.56 mmol, 1.48 eq) , PPh3 (1.36 g, 5.17 mmol, 3 eq), then the resulting mixture was purged with N2 three times and followed by the addition of DIAD (1.05 g, 5.17 mmol, 1.00 mL, 3 eq) at 0°C, then stirred at 25°C for 12 hours. The reaction mixture was partitioned between EtOAc (80 mL) and water (40 mL), washed with brine (50 mL), died over Na2SO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 0~15% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give A.4m (380 mg, 1.03 mmol, 59.53% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) d (ppm): 7.81 (d, J = 11.4 Hz, 1H), 7.48 - 7.45 (m, 1H), 7.42 - 7.40 (m, 1H), 4.28 (t, J = 6.1 Hz, 2H), 2.51 (t, J = 6.9 Hz, 2H), 2.19 - 2.08 (m, 2H), 0.15 (s, 9H). A.4n: 2,4-dichloro-8-fluoro-7-methoxy-quinoline
Figure imgf000276_0002
To a solution of 2-fluoro-3-methoxy-aniline (5 g, 35.43 mmol, 1 eq) in POCl3 (60 mL) was added malonic acid (4.2 g, 40.36 mmol, 4.20 mL, 1.14 eq), then the resulting mixture was stirred at 100°C for 12 hours. The reaction mixture was partitioned between Attorney Docket No.: 185992002240 EtOAc (250 mL, 3 times) and NaHCO3 (200 mL), water (200 mL), washed with brine (180 mL, 2 times), died over Na2SO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography (ISCO; 80 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give A.4n (3.2 g, 13.00 mmol, 36.71% yield) as a white solid. 1H NMR (400 MHz, CDCl3) d (ppm): 7.95 (d, J = 9.3 Hz, 1H), 7.50 - 7.39 (m, 2H), 4.09 (s, 3H). General procedure for Suzuki coupling reaction: Intermediates A.5 (Scheme 1; Step 4), C.1 (Scheme 3; Step 1), C.2 (Scheme 4; Step1) have been obtained following the synthetic conditions described below: A mixture of 2,4-dichloroquinoline derivative A.4 (1.0 eq), boronic ester derivatives (bor. when not commercially available) (1.2 eq), Na2CO3 (3.0 eq), Pd(PPh3)4 (0.10 eq) in S1: dioxane/H2O (0.85:0.15; 0.16M) or S2: EtOH/toluene/H2O (0.45:0.45:0.10; 0.17M) was degassed and purged with N2 three times at 25 °C, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The mixture was diluted with water and extracted with ethyl acetate (three times). The combined organic phases were washed with brine (three times), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. A.5a: 5-(4-chloro-7-methoxy-2-quinolyl)-N, N-dimethyl-pyridin-2-amine
Figure imgf000277_0001
According to Scheme 1 Step 4: 2,4-Dichloro-7-methoxy-quinoline (0.30 g, 1.3 mmol, 1.0 eq) and (6-(dimethylamino)pyridin-3-yl)boronic acid (0.26 g, 1.56 mmol, 1.2 eq) were mixed in S1 (8 mL). After work-up the residue obtained was purified by prep-TLC (SiO2, DCM/MeOH = 10:1) to give compound A.5a (0.15 g, 0.45 mmol, 35% yield, 95% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 314.1. A.5b: 2-[6-(azetidin-1-yl)-3-pyridyl]-4-chloro-6-fluoro-7-methoxy-quinoline
Figure imgf000277_0002
According to Scheme 1 Step 4: 2,4-Dichloro-6-fluoro-7-methoxy-quinoline (0.20 g, 0.81 mmol, 1.0 eq) and boronic acid bor.6 (0.17 g, 0.97 mmol, 1.2 eq) were mixed in S1 (5 Attorney Docket No.: 185992002240 mL). After work-up the residue obtained was triturated with ethyl acetate (5.0 mL) at 25 °C for 10 min to give compound A.5b (0.15 g, 0.41 mmol, 50% yield, 93% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 344.0. A.5c: 2-(azetidin-1-yl)-5-(4-chloro-7-methoxy-2-quinolyl) thiazole.
Figure imgf000278_0001
According to Scheme 1 Step 4: 2,4-dichloro-7-methoxy-quinoline (0.60 g, 2.6 mmol, 1.0 eq) and boronic ester bor.2 (0.83 g, 3.12 mmol, 1.2 eq) in S2 (15 mL). The reaction mixture was stirred at 60 °C for 16 h. After work-up the residue obtained was triturated with EtOAc (30 mL) at 25 °C for 20 min and the resulting solid was filtered and washed by EtOAc (10 mL). The filter cake was concentrated to give A.5c (0.45 g, 0.93 mmol, 35% yield, 68% purity) as yellow solid. MS m/z (ESI) [M+H]+ = 332.1. A.5d: 2-[6-(azetidin-1-yl)-3-pyridyl]-4-chloro-6,7-dimethoxy-quinoline
Figure imgf000278_0002
According to Scheme 1 Step 4: 2,4-Dichloro-6,7-dimethoxy-quinoline (0.40 g, 1.6 mmol, 1.0 eq) and boronic acid bor.6 (0.34 g, 1.92 mmol, 1.2 eq) in S1 (10 mL). After work- up the residue obtained was purified by Flash chromatography (20g column, Eluent of 0~100% EtOAc/PE gradient at 40mL/min) to give compound A.5d (0.22 g, 0.42 mmol, 27% yield, 68% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 356.0. A.5e: N-benzyl-5-(4-chloro-7-methoxy-2-quinolyl) -N- methyl-pyridin-2-amine
Figure imgf000278_0003
According to Scheme 1 Step 4: 2,4-Dichloro-7-methoxy-quinoline (0.20 g, 0.88 mmol, 1.0 eq) and (6-(benzyl(methyl)amino)pyridin-3-yl)boronic acid (0.25 g, 1.05 mmol, 1.2 eq) in S1 (5.5 mL). After work-up the residue obtained was purified by prep-TLC (Plate 1: PE/EtOAc = 3:1) to give compound A.5e (0.13 g, 0.30 mmol, 34% yield, 90% purity) as a white solid. Attorney Docket No.: 185992002240 A.5f: 2-(azetidin-1-yl)-5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl) thiazole
Figure imgf000279_0001
According to Scheme 1 Step 4: 2,4-Dichloro-6-fluoro-7-methoxy-quinoline (0.30 g, 1.2 mmol, 1.0 eq) and boronic ester bor.2 (0.38 g, 1.44 mmol, 1.2 eq) in S1 (7.5 mL). After work-up the residue obtained was purified by prep-TLC (SiO2, PE/EtOAc = 3:1) to give compound A.5f (50 mg, 0.10 mmol, 8.2% yield, 70% purity) as yellow oil. MS m/z (ESI) [M+H]+ = 350.0. A.5g: 2-[6-(azetidin-1-yl)-3-pyridyl]-4-chloro-6-fluoro-N, N-dimethyl-quinolin-7-amine
Figure imgf000279_0002
According to Scheme 1 Step 4: 2,4-Dichloro-6-fluoro-N, N-dimethyl-quinolin-7- amine (0.17 g, 0.66 mmol, 1.0 eq) and boronic acid bor.6 (0.14 g, 0.8 mmol, 1.2 eq) in S1 (10 mL). After work-up the residue obtained was purified by Flash chromatography (12 g column, Eluent of 0~20% EtOAc/PE gradient at 45 mL/min) to give compound A.5g (0.12 g, 0.30 mmol, 46% yield, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+ = 357.1. A.5h: N-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl) phenyl] acetamide
Figure imgf000279_0003
According to Scheme 1 Step 4: To a mixture of 2, 4-dichloro-6-fluoro-7-methoxy- quinoline (0.20 g, 0.81 mmol, 1.0 eq) in dioxane (3.0 mL) / H2O (0.30 mL) was added N-[4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]acetamide (0.21 g, 0.80 mmol, 0.99 eq), Pd(PPh3)2Cl2 (60 mg, 85 μmol, 0.11 eq) and Na2CO3 (0.26 g, 2.5 mmol, 3.0 eq), then the mixture was stirred at 60 °C under N2 for 12 h. The reaction mixture was filtered and concentrated the filter liquor. The residue obtained was purified by flash chromatography (12 g column, Eluent of 0 to 50% EtOAc/PE gradient at 20 mL/min) to afford A.5h (0.11 g, 0.30 mmol, 37% yield, 94% purity) as yellow oil. MS m/z (ESI) [M+H] + = 345.1. Attorney Docket No.: 185992002240 A.5i: 1-[4-[5-(4-chloro-6,7-dimethoxy-2-quinolyl)-2-pyridyl] piperazin-1-yl] ethanone
Figure imgf000280_0001
According to Scheme 1 Step 4: 2,4-Dichloro-6,7-dimethoxy-quinoline (0.25 g, 0.97 mmol, 1.0 eq) and (6-(4-acetylpiperazin-1-yl)pyridin-3-yl)boronic acid (0.29 g, 1.16 mmol, 1.2 eq) in S1 (6 mL). After work-up the residue obtained was purified by prep-TLC (SiO2, PE/EtOAc = 1:1) to give compound A.5i (0.27 g, 0.59 mmol, 61% yield, 94% purity) was obtained as a brown solid. MS m/z (ESI) [M+H] + = 427.1. A.5j: 2-(6-(4-benzylpiperazin-1-yl) pyridin-3-yl)-4-chloroquinoline
Figure imgf000280_0002
A solution of C.1a (33 g, 78 mmol, 1.0 eq) in EtOAc (0.10 L) was degassed and purged with N2 three times. HCl/EtOAc (2.0 M, 0.50 mL, 13 eq) was added dropwise under N2. The reaction mixture was stirred at room temperature for 1 h under N2. The reaction mixture was filtered and gave the HCl.salt (40 g, crude) as a yellow solid. To the crude (70 g from two batches) was added H2O (1.0 L) at room temperature. pH was adjusted to 11~12 with saturated K2CO3 aqueous solution. The mixture was extracted with EtOAc (1.0 L, four times) and concentrated under vacuum. The crude product (around 40 g) was triturated with MTBE at room temperature for 12 h to obtain 4-chloro-2-(6-(piperazin-1-yl)pyridin-3- yl)quinoline A.5k (34 g, 0.10 mol, 60% yield, 96% purity) was obtained as a light yellow solid. MS m/z (ESI) [M+H]+ = 325.0. 1H NMR (400 MHz, CDCl3) d (ppm): 8.92 (d, J = 2.4 Hz, 1H), 8.35 (dd, J = 2.4, 8.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.7-7.8 (m, 1H), 7.57 (t, J = 7.6 Hz, 1H), 6.76 (d, J = 9.2 Hz, 1H), 3.6-3.7 (m, 4H), 3.0-3.1 (m, 4H). Free amine A.5k (1.5 g, 4.6 mmol, 1.0 eq) was mixed with cesium carbonate (3.0 g, 9.2 mmol, 2.0 eq) and (chloromethyl)benzene (0.64 mL, 5.5 mmol, 1.2 eq) in 100 mL flask. DMF (37 mL) was added, and the reaction was stirred at room temperature for 3 days. The reaction mixture was transferred to a 0.50 L flask and diluted with EtOAc (0.20 L) and Attorney Docket No.: 185992002240 washed with water (0.20 L) and brine (0.20 L). The crude material was obtained as 2.7 g of yellow oil. The oil was diluted with DCM (4.0 mL) and subjected to purification by fully automated flash chromatography (heptane/EtOAc, 0–40% in 0–15 CV). Compound A.5j (0.71 g, 1.7 mmol, 37% yield) was obtained as yellow solid. 1H NMR (400 MHz, CDCl3) d (ppm): 8.96 (d, J = 2.4 Hz, 1H), 7.50–8.05 (m, 6H), 7.39 (s, 5H), 6.79 (d, J = 9.0 Hz, 1H), 3.73 (t, J = 5.6 Hz, 4H), 3.63 (s, 2H), 2.63 (t, J = 5.1 Hz, 4H). A.5k: 2-(azetidin-1-yl)-5-(7-bromo-4-chloro-2-quinolyl)thiazole
Figure imgf000281_0001
According to Scheme 1 Step 4: 7-bromo-2,4-dichloro-quinoline (500 mg, 1.81 mmol, 1 eq) and 2-(azetidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (480.54 mg, 1.81 mmol, 1 eq) in S1 (1 mL). After work-up the residue was triturated with Petroleum ether : Ethyl acetate (1:1, 5 ml) at 25 oC for 0.5 hours to give A.5k (250 mg, 591.03 μmol, 32.74% yield, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 381.9. A.5l: 2-[6-(azetidin-1-yl)-3-pyridyl]-4-chloro-7-methoxy-quinoline
Figure imgf000281_0002
According to Scheme 1 Step 4: 2, 4-dichloro-7-methoxy-quinoline (200 mg, 876.91 μmol, 1 eq) and 2-(azetidin-1-yl) -5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (230 mg, 884.14 μmol, 1.01 eq) in S1 (3.2 mL). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 40~60% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to afford A.5l (250 mg, 736.67 μmol, 84.01% yield, 96% purity) as yellow oil. A.5m: 4-chloro-6-fluoro-7-methoxy-2-(6-pyrrolidin-1-yl-3-pyridyl)quinoline
Figure imgf000281_0003
According to Scheme 1 Step 4: To a screw-cap vial equipped with a magnetic stir bar was added 2, 4-dichloro-6-fluoro-7-methoxy-quinoline (600 mg, 2.44 mmol, 1 eq) and dioxane (10 mL) and H2O (2 mL) and 2-pyrrolidin-1-yl-5-(4, 4, 5, 5-tetramethyl-1, 3, 2- Attorney Docket No.: 185992002240 dioxaborolan-2-yl) pyridine (670 mg, 2.44 mmol, 1 eq) and Na2CO3 (800 mg, 7.55 mmol, 3.10 eq) and Pd(PPh3)4 (280 mg, 242 μmol, 0.1 eq) sequentially. The vial was sealed with a teflon-lined septum, evacuated and backfilled with nitrogen. Then the mixture was stirred at 80 °C for 16 hours under nitrogen atmosphere. TLC (Petroleum ether/Ethylacetate=1/1, NH3.H2O, Rf=0.43) indicated new spots formed. The reaction mixture was quenched by water (10 mL) and EtOAc (10 mL), and then the resulting mixture was filtered and the filter cake was concentrated in vacuum to give A.5m (650 mg, 1.82 mmol, 74.5% yield) as white solid. A.5n: 2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]-N,N-dimethyl-ethanamine
Figure imgf000282_0001
According to Scheme 1 Step 4: A mixture of N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenoxy]ethanamine (2.95 g, 3.04 mmol, 9.97e-1 eq), 2,4-dichloro- 6-fluoro-7-methoxy-quinoline (750 mg, 3.05 mmol, 1 eq), Pd(PPh3)4 (352 mg, 304.61 μmol, 9.99e-2 eq) and Na2CO3 (969 mg, 9.14 mmol, 3 eq) in S2 (22 mL). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give A.5n (1 g, 2.29 mmol, 75.19% yield, 85.9% purity) as a brown solid. MS m/z (ESI) [M+H] + = 375.1. C.1a: tert-butyl 4-[5-(4-chloro-2-quinolyl) -2-pyridyl] piperazine-1-carboxylate
Figure imgf000282_0002
According to Scheme 3 Step 1: 2,4-Dichloroquinoline (0.35 g, 1.8 mmol, 1.0 eq) and (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)boronic acid (0.66 g, 2.16 mmol, 1.2 eq) in S1 (11.25 mL). After work-up the residue was purified by Flash chromatography (40 g column, Eluent of 0-21% EtOAc/PE gradient at 40 mL/min) to give C.1a (0.65 g, 1.5 mmol, 87% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) d (ppm): 8.95 - 8.92 (m, 1H), 8.41 - 8.36 (m, 1H), 8.23 - 8.18 (m, 1H), 8.14 - 8.09 (m, 1H), 7.90 - 7.88 (m, 1H), 7.78 - 7.73 (m, 1H), 7.62 - 7.56 (m, 1H), 6.80 - 6.75 (m, 1H), 3.72 - 3.65 (m, 4H), 3.63 - 3.56 (m, 4H), 1.53 - 1.49 (m, 9H). Attorney Docket No.: 185992002240 C.1b: tert-butyl 4-[4-(4-chloro-2-quinolyl) phenyl] piperazine-1-carboxylate
Figure imgf000283_0001
According to Scheme 3 Step 1: 2,4-Dichloroquinoline (2.0 g, 10 mmol, 1.0 eq) and (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (3.67 g, 12 mmol, 1.2 eq) in S1 (62.5 mL). After work-up the residue obtained was purified by column chromatography (SiO2, PE/EtOAc = 20/1 to 3/1) to afford C.1b (3.0 g, 7.1 mmol, 70% yield) as a yellow solid. MS m/z (ESI) [M+H]+= 424.2. C.1c: tert-butyl 4- [5-(4-chloro-6, 7-dimethoxy-2-quinolyl) -2-pyridyl] piperazine-1- carboxylate
Figure imgf000283_0002
According to Scheme 3 Step 1: 2,4-Dichloro-6,7-dimethoxy-quinoline (0.20 g, 0.77 mmol, 1.0 eq) and (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)boronic acid (0.28 g, 0.92 mmol, 1.2 eq) in S1 (4.8 mL). After work-up the residue obtained was purified by Flash chromatography (20 g column, Eluent of 0~50% EtOAc/PE gradient at 30 mL/min) to afford C.1c (0.35 g, 0.59 mmol, 76% yield, 82% purity) as yellow gum. MS m/z (ESI) [M+H]+= 485.2. C.1e: tert-butyl 4-[5-(4-chloro-7-methoxy-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate
Figure imgf000283_0003
According to Scheme 3 Step 1: 2,4-Dichloro-7-methoxy-quinoline (0.30 g, 1.3 mmol, 1.0 eq) and (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)boronic acid (0.48 g, 1.56 mmol, 1.2 eq) in S1 (8.1 mL). After work-up the residue obtained was purified by prep-TLC (SiO2, PE/EtOAc = 2:1) to give C.1e (0.50 g, 1.0 mmol, 77% yield, 92% purity) was obtained as yellow oil. MS m/z (ESI) [M+H]+= 455.2. Attorney Docket No.: 185992002240 C.1f: tert-butyl 4-[4-(4-chloro-7-methoxy-2-quinolyl) phenyl] piperazine-1-carboxylate
Figure imgf000284_0001
According to Scheme 3 Step 1: 2,4-Dichloro-7-methoxy-quinoline (0.40 g, 1.8 mmol, 1.0 eq) and (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (0.66 g, 2.16 mmol, 1.2 eq) in S1 (11.25 mL). After work-up the residue obtained was purified by Flash chromatography (12 g column, Eluent of 20~30% EtOAc/PE gradient at 40 mL/min) to afford C.1f (0.60 g, 1.3 mmol, 75% yield, 99% purity) as yellow oil. MS m/z (ESI) [M+H]+ = 454.2. C.1g: tert-butyl 3-[5-(4-chloro-7-methoxy-2-quinolyl)-2-pyridyl] azetidine-1-carboxylate
Figure imgf000284_0002
According to Scheme 3 Step 1: 2,4-Dichloro-7-methoxy-quinoline (0.40 g, 1.8 mmol, 1.0 eq), boronic acid bor.1’ (0.48 g, 2.16 mmol, 1.2 eq) in S1 (11.25 mL). After work-up the residue obtained was purified by Flash chromatography (40g column, Eluent of 0~10% EtOAc/PE gradient at 40 mL/min) to afford C.1g (0.36 g, 0.74 mmol, 42% yield, 88% purity) as yellow oil. MS m/z (ESI) [M+H]+= 426.1. C.1h: tert-butyl N- [2- [4- [4-chloro-7-(dimethylamino)-6-methoxy-2-quinolyl] phenoxy] ethyl]-N-methylcarbamate
Figure imgf000284_0003
2,4-Dichloro-6-methoxy-N, N-dimethyl-quinolin-7-amine (0.15 g, 0.55 mmol, 1.0 eq) and tert-butyl methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)ethyl)carbamate (0.25 g, 0.66 mmol, 1.2 eq) in S1 (3.44 mL). After work-up the residue obtained was purified by prep-TLC (SiO2, PE/EtOAc = 2:1) to give C.1h (0.16 g, 0.33 mmol, 60% yield, 100% purity) as a yellow oil. MS m/z (ESI) [M+H]+= 486.3. Attorney Docket No.: 185992002240 C.1i: tert-butyl 4-[5-[4-chloro-7-(dimethylamino)-2-quinolyl]-2-pyridyl] piperazine-1- carboxylate
Figure imgf000285_0001
According to Scheme 3 Step 1: 2,4-Dichloro-N, N-dimethyl-quinolin-7-amine A.4d (0.50 g, 2.1 mmol, 1.0 eq) and (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)boronic acid (0.77 g, 2.52 mmol, 1.2 eq) in S1 (13.1 mL). After work-up the residue obtained was not purified. C.1i (0.80 g, 1.2 mmol, 58% yield, 70% purity) was obtained as a yellow solid. MS m/z (ESI) [M+H]+= 468.2. C.1j: tert-butyl N-[2- chloro-7-(dimethylamino)-2-quinolyl]-2-pyridyl] oxy] ethyl]-N-
Figure imgf000285_0002
methylcarbamate
Figure imgf000285_0003
According to Scheme 3 Step 1: 2,4-Dichloro-N, N-dimethyl-quinolin-7-amine A.4d (0.30 g, 1.2 mmol, 1.0 eq) and tert-butyl methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenoxy)ethyl)carbamate (054 g, 1.44 mmol, 1.2 eq) in S1 (7.5 mL). After work-up the residue obtained was not purified. C.1j (0.80 g, 1.2 mmol, 98% yield, 70% purity) as a yellow solid. MS m/z (ESI) [M+H] += 457.2. C.1k: tert-butyl N-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]-N- methylcarbamate
Figure imgf000285_0004
According to Scheme 3 Step 1: 2,4-Dichloro-6-fluoro-7-methoxy-quinoline (0.45 g, 1.8 mmol, 1.0 eq) and tert-butyl methyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl)carbamate (0.72 g, 2.16 mmol, 1.2 eq) in S1 (11.2 mL). After work-up the residue obtained was purified by Flash chromatography (12 g column, Eluent of 0~20% EtOAc/PE gradient at 40 mL/min) to afford C.1k (0.60 g, 1.2 mmol, 64% yield, 82% purity) as a light green solid. MS m/z (ESI) [M+H]+= 418.1. Attorney Docket No.: 185992002240 C.1l: tert-butyl 4-[5-[4-chloro-7-(dimethylamino)-6-fluoro-2-quinolyl]-2-pyridyl] piperazine- 1-carboxylate
Figure imgf000286_0001
According to Scheme 3 Step 1: 2,4-Dichloro-6-fluoro-N, N-dimethyl-quinolin-7- amine (0.30 g, 1.2 mmol, 1.0 eq) and (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3- yl)boronic acid (0.44 g, 1.44 mmol, 1.2 eq) in S1 (7.5 mL). After work-up the residue obtained was purified by Flash chromatography (12 g column, Eluent of 0 to 15% EtOAc/PE gradient at 45 mL/min) to give C.1l (0.50 g, 0.84 mmol, 73% yield, 82% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 486.2. C.1m: tert-butyl N-[2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl) phenoxy] ethyl]-N- methylcarbamate
Figure imgf000286_0002
According to Scheme 3 Step 1: 2,4-Dichloro-6-fluoro-7-methoxy-quinoline (0.30 g, 1.2 mmol, 1.0 eq) and tert-butyl methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)ethyl)carbamate (0.54 g, 1.44 mmol, 1.2 eq) in S1 (7.5 mL). After work-up the residue obtained was purified by silica gel chromatography (Biotage, 100-200 mesh silica gel, product came out at B = 25% EtOAc/PE) to afford product C.1m (0.50 g, 1.1 mmol, 89% yield) as off-white solid. C.1n: tert-butyl N- (4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]oxy]ethyl]-N-
Figure imgf000286_0003
cyclopropyl-
Figure imgf000286_0004
According to Scheme 3 Step 1: 2,4-Dichloro-6-fluoro-7-methoxy-quinoline (0.18 g, 0.73 mol, 1.0 eq) and tert-butyl N-cyclopropyl-N-[2-[[5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-pyridyl]oxy]ethyl]carbamate (0.36 g, 0.88 mmol, 1.2 eq) in S1 (4.6 mL). After work-up the residue obtained was purified by Flash chromatography (20 g Attorney Docket No.: 185992002240 column, Eluent of 0~30% EtOAc/PE gradient at 30 mL/min) to give C.1n (0.12 g, 0.17 mmol, 23% yield, 69% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 488.2. C.1o: tert-butyl N-[2-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]-1-methyl-2- oxo-ethyl] carbamate
Figure imgf000287_0001
According to Scheme 3 Step 1: 2,4-Dichloro-6-fluoro-7-methoxy-quinoline (0.30 g, 1.2 mmol, 1.0 eq) and tert-butyl N-[1-methyl-2-oxo-2-[5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-pyridyl] ethyl] carbamate (0.54 g, 1.44 mmol, 1.2 eq) in S1 (7.5 mL). After work-up the residue obtained was purified by Flash chromatography (20 g column, Eluent of 0~23% EtOAc/PE gradient at 60 mL/min) to give desired compound as a yellow solid, which was further triturated with EtOAc (50 mL) at 25 °C for 10 min, the resulting solid was filtered and washed by EtOAc (50 mL), the filter cake was concentrated to give C.1o (0.30 g, 0.65 mmol, 53% yield, 99% purity) as an off-white solid. C.1p: tert-butyl N-[5-(7-bromo-4-chloro-2-quinolyl) -2-pyridyl]-N-methylcarbamate
Figure imgf000287_0002
According to Scheme 3 Step 1: 7-Bromo-2,4-dichloro-quinoline A.4h (0.30 g, 1.1 mmol, 1.0 eq) and tert-butyl methyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin- 2-yl)carbamate (0.44 g, 1.32 mmol, 1.2 eq) in S1 (6.9 mL). After work-up the residue obtained was purified by Flash chromatography (12 g column, Eluent of 0~10% EtOAc/PE gradient at 40 mL/min) to afford C.1p (0.30 g, 0.66 mmol, 60% yield, 98% purity) as a white solid. MS m/z (ESI) [M+H]+= 450.0. C.1q: tert-butyl N-[2-[4-[5-(4-chloro-7-methoxy-2-quinolyl)-2-pyridyl] piperazin-1-yl]-1- methyl-2-oxo-ethyl] carbamate
Figure imgf000287_0003
Attorney Docket No.: 185992002240 According to Scheme 3 Step 1: 2,4-Dichloro-7-methoxy-quinoline (0.25 g, 1.1 mmol, 1.0 eq),and [6-[4-[2-(tert-butoxycarbonylamino) propanoyl] piperazin-1-yl]-3-pyridyl] boronic acid bor.7 (0.52 g, 1.3 mmol, 1.2 eq) in S1 (6.9 mL). The crude product was triturated with EtOAc (30 mL) (at 25 °C for 30 min to give C.1q (0.23 g, 0.41 mmol, 37% yield, 94% purity). MS m/z (ESI) [M+H]+= 526.2. C.1r: tert-butyl 4-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl] piperazine-1- carboxylate
Figure imgf000288_0001
According to Scheme 3 Step 1: 2,4-Dichloro-6-fluoro-7-methoxy-quinoline (0.30 g, 1.2 mmol, 1.0 eq) and (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)boronic acid (0.44 g, 1.44 mmol, 1.2 eq) in S1 (7.5 mL). After work-up the residue obtained was purified by Flash chromatography (40g column, Eluent of 0~25% EtOAc/PE gradient at 40 mL/min) to afford C.1r (0.55 g, 0.95 mmol, 78% yield, 82% purity) as yellow oil. MS m/z (ESI) [M+H]+= 473.2. C.1s: tert-butyl methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)ethyl)carbamate
Figure imgf000288_0002
According to Scheme 3 Step 1: 2,4-Dichloro-7-methoxy-quinoline (0.30 g, 1.3 mmol, 1.0 eq) and tert-butyl methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)ethyl)carbamate (0.59 g, 1.56 mmol, 1.2 eq) in S1 (8.12 mL). After work-up the residue obtained was purified by Flash chromatography (20 g column, EtOAc/PE 0 to 21% at 60 mL/min) to give C.1s (0.60 g, 0.81 mmol, 62% yield, 60% purity) as a colourless gum. C.1t: tert-butyl (1-(4-(4-(4-chloro-7-methoxyquinolin-2-yl) phenyl) piperazin-1-yl)-1- oxopropan-2-yl) carbamate
Figure imgf000288_0003
Attorney Docket No.: 185992002240 According to Scheme 3 Step 1: 2,4-Dichloro-7-methoxy-quinoline (0.10 mg, 0.44 mmol, 1.0 eq eq) and tert-butyl (1-oxo-1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazin-1-yl)propan-2-yl)carbamate (0.24 g, 0.53 mmol, 1.2 eq) in S1 (2.8 mL). The crude product was triturated with Ethyl acetate (20 mL) at 25 °C for 20 min to give C.1t (0.13 mg, 0.25 mmol, 56% yield, 100% purity) was obtained as a yellow solid. MS m/z (ESI) [M+H]+= 525.2. C.1u: tert-butyl-[2-[4-[5-(4-chloro-6,7-dimethoxy-2-quinolyl)-2-pyridyl] piperazin-1-yl] ethoxy]-dimethyl-silane
Figure imgf000289_0001
To a solution of compound C.1c (0.68 g, 1.4 mmol, 1.0 eq) in dioxane (2.0 mL) was added HCl/dioxane (4.0 M, 5.0 mL) at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give 4-chloro-6,7-dimethoxy-2- (6-piperazin-1-yl-3-pyridyl) quinoline (0.17 g, 0.44 mmol, 77% yield, 100% purity), which was obtained as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.56 (s, 2H), 9.00 (d, J = 2.1 Hz, 1H), 8.64 (d, J = 7.8 Hz, 1H), 8.32 (s, 1H), 7.78 (s, 1H), 7.40 (s, 1H), 7.27 (d, J = 9.3 Hz, 1H), 4.00 (s, 10H), 3.24 (s, 4H). MS m/z (ESI) [M+H] += 385.1. To a solution of 4-chloro-6,7-dimethoxy-2-(6-piperazin-1-yl-3-pyridyl) quinoline (0.14 g, 0.36 mmol, 1.0 eq) in DMF (2.0 mL) was added 2-bromoethoxy-tert-butyl-dimethyl- silane (0.14 g, 0.59 mmol, 1.6 eq) and K2CO3 (0.21 g, 1.5 mmol, 4.2 eq) at 25 °C. The mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (25 mL, three times). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, PE/EtOAc = 1:1) to give C.1u (0.14 g, 0.25 mmol, 69% yield, 98% purity) was obtained as a yellow oil. MS m/z (ESI) [M+H] += 543.3. Attorney Docket No.: 185992002240 C.1v: tert-butyl-[2-[4-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl] piperazin-1- yl] ethoxy]-dimethyl-silane
Figure imgf000290_0001
To a solution of C.1r (0.19 g, 0.40 mmol, 1.0 eq) in dioxane (2.0 mL) was added HCl/dioxane (2.0 M, 5.0 mL, 25 eq). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give 4-chloro-6-fluoro-7-methoxy-2-(6-piperazin-1-yl-3-pyridyl) quinoline (0.14 g, 0.38 mmol, 93% yield) as a white solid. The crude material was used in the next step without purification. MS m/z (ESI) [M+H] += 373.1. To a solution of 4-chloro-6-fluoro-7-methoxy-2-(6-piperazin-1-yl-3-pyridyl) quinoline (0.13 g, 0.35 mmol, 1.0 eq) and 2-bromoethoxy-tert-butyl-dimethyl-silane (0.17 g, 0.71 mmol, 2.0 eq) in DMF (5.0 mL) was added K2CO3 (0.10 g, 0.75 mmol, 2.2 eq) at 25 °C. The mixture was stirred at 60 °C for 5 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL, three times). The combined organic phases were washed with brine (50 mL, three times), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue obtained was purified by prep-HPLC 2 (gradient: 34%-64% B over 10 min) to give C.1v (0.15 g, 0.19 mmol, 55% yield, 68% purity) as a white solid. MS m/z (ESI) [M+H]+= 531.3. C.1w: tert-butyl 4-[5-(6-bromo-4-chloro-7-methoxy-2-quinolyl)-2-pyridyl] piperazine-1- carboxylate
Figure imgf000290_0002
To a mixture of 6-bromo-2,4-dichloro-7-methoxy-quinoline (0.40 g, 1.3 mmol, 1.0 eq) and tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine-1- carboxylate (0.51 g, 1.3 mmol, 1.0 eq) in S2 (7.65 mL) was added Pd(PPh3)4 (0.10 eq), sodium carbonate (2.0 eq). The mixture was stirred at 70 °C for 16 h. After work-up the residue was purified by Flash chromatography (12 g column, Eluent of 0 to 30% EtOAc/PE gradient at 40 mL/min) to give C.1w (0.34 g, 0.57 mmol, 44%, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 535.1. Attorney Docket No.: 185992002240 C.1x: tert-butyl (1-(4-(5-(4-chloro-6-fluoro-7-methoxyquinolin-2-yl) pyridin-2-yl) piperazin- 1-yl)-1-oxopropan-2-yl) carbamate
Figure imgf000291_0001
C.1r (0.55 g, 1.2 mmol, 1.0 eq) was added to HCl/dioxane (2.0 M, 5.0 mL, 8.6 eq) and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated to give 4-chloro-6-fluoro-7-methoxy-2-(6-piperazin-1-yl-3-pyridyl) quinoline (0.43 g, 1.2 mmol, 99% yield) as yellow solid, which was used in next step directly without further purification. To a solution of 4-chloro-6-fluoro-7-methoxy-2-(6-piperazin-1-yl-3-pyridyl)quinoline (0.20 g, 0.54 mmol, 1.0 eq) in DMF (10 mL) was added 2-(tert- butoxycarbonylamino)propanoic acid (0.16 g, 0.85 mmol, 1.6 eq), HATU (0.32 g, 0.84 mmol, 1.6 eq) and DIEA (0.22 g, 1.7 mmol, 0.30 mL, 3.2 eq). The reaction mixture was stirred at 25 °C for 1 h. The reaction was poured into water (0.10 L), extracted with EtOAc (0.10 L, three times). The combined organic phases were washed with saturated brine (100 mL, twice), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with EtOAc (30 mL) at 25 oC for 20 min and the resulting solid was filtered and washed by EtOAc (10 mL), the filter cake was concentrated to give C.1x (0.25 g, 0.44 mmol, 82% yield, 96% purity) as white solid. MS m/z (ESI) [M+H]+= 544.2. C.1y: tert-butyl N-[2-[5-[4-chloro-7-(dimethylamino)-6-fluoro-2-quinolyl]-2-pyridyl]-1- methyl-2-oxo-ethyl] carbamate
Figure imgf000291_0002
According to Scheme 3 Step 1: To a solution of 2,4-dichloro-6-fluoro-N,N-dimethyl- quinolin-7-amine (0.10 g, 0.39 mmol, 1.0 eq) and tert-butyl N-[1-methyl-2-oxo-2-[5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]ethyl]carbamate (0.28 g, 0.74 mmol, 1.9 eq) in dioxane (4.0 mL) / H2O (0.40 mL) was added Pd(PPh3)4 (45 mg, 39 μmol, 0.10 eq) and Na2CO3 (0.12 g, 1.2 mmol, 3.0 eq) at 25 °C. After stirring at 60 °C for 16 h, the reaction mixture filtered and concentrated under reduced pressure. The residue obtained was purified Attorney Docket No.: 185992002240 by prep-TLC (SiO2, PE/EtOAc = 5:1) to give C.1y (0.90 g, 0.17 mmol, 44% yield, 90% purity) as a yellow oil. MS m/z (ESI) [M+H]+= 473.1. C.1z: tert-butyl N-[2- chloro-6-fluoro-2-quinolyl)-2-pyridyl]oxy] ethyl]-N-methyl
Figure imgf000292_0001
carbamate
Figure imgf000292_0002
According to Scheme 3 Step 1: To a solution of 2, 4-dichloro-6-fluoro-quinoline (0.20 g, 0.93 mmol, 1.0 eq) and tert-butyl N-methyl-N-[2-[[5-(4, 4, 5, 5-tetramethyl-1, 3, 2- dioxaborolan-2-yl) -2-pyridyl]oxy]ethyl]carbamate (0.35 g, 0.93 mmol, 1.0 eq) in S1 (5.8 mL) was added Pd(PPh3)4 (0.09 eq) and Na2CO3 (2.0 eq). Then the resulting mixture was stirred at 60 °C for 16 h under N2. After work-up the residue obtained was purified by flash chromatography (20 g column, Eluent of 0 to 80% EtOAc/PE gradient at 40 mL/min) to give C.1z (0.30 g, 0.57 mmol, 61% yield, 82% purity) as colorless gum. MS m/z (ESI) [M+Na]+= 454.3. C.1aa: tert-butyl N-[2-[[5-(4-chloro-6, 7-difluoro-2-quinolyl)-2-pyridyl]oxy]ethyl]-N- methyl-carbamate
Figure imgf000292_0003
According to Scheme 3 Step 1: To a solution of A.4i (0.32 g, 0.85 mmol, 0.99 eq) and tert-butyl methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)carbamate bor.3 (0.39 g, 1.02 mmol, 1.2 eq) in S2 (5 mL) was added Pd(PPh3)4 (0.10 g, 87 mmol, 0.10 eq) and sodium carbonate (0.19 g, 1.8 mmol, 2.0 eq) at 25 °C. The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 60 °C for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by prep-TLC (PE/EtOAc= 0:1) to give C.1aa (0.18 g, 0.36 mmol, 42% yield, 90% purity) as a yellow solid. Attorney Docket No.: 185992002240 C.1ab: tert-butyl N-[1- (4-chloro-6-fluoro-7-methoxy-2-quinolyl) phenyl] carbamoyl]-2-
Figure imgf000293_0001
methyl-propyl] carbamate
Figure imgf000293_0003
According to Scheme 3 Step 1: To a solution of 2, 4-dichloro-6-fluoro-7-methoxy- quinoline (0.20 g, 0.82 mmol, 1.0 eq) and bor.8 (0.45 g, 0.99 mmol, 1.2 eq) in dioxane (4.0 mL) /H2O (0.40 mL) was added Pd(PPh3)4 (0.10 g, 87 μmol, 0.11 eq) and Na2CO3 (0.20 g, 1.9 mmol, 2.3 eq), then the resulting mixture was stirred at 80 °C for 12 h under N2. The reaction mixture was diluted with EtOAc (50 mL), washed with water (20 mL, twice). The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give a crude material. The residue obtained was purified by Flash chromatography (4.0 g column, gradient: 0 to 100% EtOAc/PE at 20 mL/min) to give C.1ab (0.29 g, 0.56 mmol, 69% yield, 97% purity) as colorless gum. MS m/z (ESI) [M+H]+= 502.4. C.1ac: tert-butyl N-[2-[4-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl] piperazin- 1-yl]-1,1-dimethyl-2-oxo-ethyl] carbamate
Figure imgf000293_0002
To a solution of 4-chloro-6-fluoro-7-methoxy-2-(6-piperazin-1-yl-3-pyridyl)quinoline (0.20 g, 0.54 mmol, 1.0 eq) in DMF (10 mL) was added 2-(tert-butoxycarbonylamino)-2- methyl-propanoic acid (0.17 g, 0.84 mmol, 1.6 eq), HATU (0.32 g, 0.84 mmol, 1.6 eq) and DIEA (0.22 g, 1.7 mmol, 0.30 mL, 3.2 eq). The reaction mixture was stirred at 25 °C for 12 h. Then the reaction was poured into water (0.10 L), extracted with EtOAc (50 mL, three times). The combined organic phases were washed with saturated brine (50 mL, twice), dried over anhydrous Na2SO4, filtered, and concentrated. The residue obtained was purified by Flash chromatography (40 g column, gradient: 0 to 10% EtOAc/PE at 40 mL/min) to afford C.5ac (0.20 g, 0.34 mmol, 63% yield, 94% purity) as red oil. MS m/z (ESI) [M+H]+= 558.2. Attorney Docket No.: 185992002240 C.1ad: tert-butyl N-[5-(4, 7-dichloro-2-quinolyl) -2-pyridyl]-N-methyl-carbamate
Figure imgf000294_0001
According to Scheme 3 Step 1: To a solution of 2, 4, 7-trichloroquinoline (0.30 g, 1.3 mmol, 1.0 eq) and tert-butyl N-methyl-N-[5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyridyl]carbamate (0.40 g, 1.2 mmol, 0.93 eq) in S2 (7.64 mL) were added Pd(PPh3)4 (0.15 g, 0.13 mmol, 0.10 eq) and Na2CO3 (0.28 g, 2.6 mmol, 2.1 eq) at 25 °C. The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 60 °C for 12 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (4 g column, gradient 0 to 10% EtOAc/PE at 30 mL/min) to give C.1ad (0.40 g, 0.94 mmol, 73% yield, 95% purity) as a white solid. C.1ae: tert-butyl (2-((5-(4-chloro-7-methoxyquinolin-2-yl)pyridin- 2l)oxy)ethyl)(methyl)carbamate
Figure imgf000294_0002
According to Scheme 3 Step 1: 2,4-Dichloro-7-methoxy-quinoline (0.30 g, 1.3 mmol, 1.0 eq) and tert-butyl methyl(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl)oxy)ethyl)carbamate bor.3 (0.46 g, 1.56 mmol, 1.2 eq) in S1 (8.12 mL). After work-up the residue obtained was purified by Flash chromatography (20 g column, EtOAc/PE 0 to 21% at 60 mL/min) to give product C.1ae (0.60 g, 0.81 mmol, 60% yield, 65% purity) as a colourless gum. C.1af: tert-butyl N-[2-[4-[4-chloro-6-fluoro-7-(trideuteriomethoxy)-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000294_0003
According to Scheme 3 Step 1: To a solution of 2,4-dichloro-6-fluoro-7- (trideuteriomethoxy)quinoline (200 mg, 802.94 μmol, 1 eq) in S1 (6 mL) was added tert-butyl N-methyl-N-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate Attorney Docket No.: 185992002240 (300 mg, 795.16 μmol, 0.99 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to afford C.af (350 mg, 703.10 μmol, 87.57% yield, 93.2% purity) as red oil. MS m/z (ESI) [M+H]+= 464.2. C.1ag: tert-butyl N-[2-[4-[4-chloro-7-(dimethylamino)-6-fluoro-2-quinolyl]phenyl]-1- methyl-2-oxo-ethyl]carbamate
Figure imgf000295_0001
To a solution of 2,4-dichloro-6-fluoro-N,N-dimethyl-quinolin-7-amine (300 mg, 1.16 mmol, 1 eq), tert-butyl N-[1-methyl-2-oxo-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]ethyl] carbamate (521.39 mg, 1.39 mmol, 1.2 eq) in S1 (6.6 mL). After work-up residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate= 1:1) to give C.1ag (0.3 g, 572.09 μmol, 49.41% yield, 90% purity) as a yellow solid. C.1ah: tert-butyl N-[2-[4-[4-chloro-6-fluoro-7-(5-trimethylsilylpent-4-ynoxy)-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000295_0002
According to Scheme 3 Step 1: To a solution of 5-[(2,4-dichloro-6-fluoro-7- quinolyl)oxy]pent-1-ynyl-trimethyl-silane (370 mg, 999.14 μmol, 1 eq) in S1 (8.5 mL) was added tert-butyl N-methyl-N-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]ethyl]carbamate (460 mg, 1.22 mmol, 1.22 eq). After work-up the crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.1ah (300 mg, 470.62 μmol, 47.10% yield, 91.8% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 585.2. C.1ai: tert-butyl N-[2- (4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]amino]-1,1-
Figure imgf000295_0003
dimethyl-2-oxo-ethyl]carbamate
Figure imgf000295_0004
Attorney Docket No.: 185992002240 Step 1: To a screw-cap vial equipped with a magnetic stir bar was added 2, 4- dichloro-6-fluoro-7-methoxy-quinoline (500 mg, 2.03 mmol, 1 eq) and tert-butyl N-[5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyridyl]carbamate (640 mg, 2.00 mmol, 0.98 eq) and dioxane (7.5 mL) and H2O (1.5 mL) and Na2CO3 (700 mg, 6.60 mmol, 3.2 eq) and Pd(PPh3)4 (240 mg, 207 μmol, 0.1 eq) sequentially. The vial was sealed with a teflon-lined septum, evacuated and backfilled with nitrogen. Then the mixture was stirred at 90 °C for 16 hours under nitrogen atmosphere. The reaction mixture was quenched by water (10 mL) and EtOAc (10 mL) and then filtered. The filter cake was collected as tert-butyl N-[5-(4-chloro-6- fluoro-7-methoxy-2-quinolyl) -2-pyridyl]carbamate (530 mg, 1.31 mmol, 64.5% yield). After work-up the residue was purified by silica gel chromatography (Biotage, 100-200 mesh silica gel, product came out at B=10%. A: Petroleum ether, B: Ethyl acetate) to afford tert-butyl N- [5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]carbamate (70 mg, 173 μmol, 8.5% yield). 1H NMR (400 MHz, DMSO-d6) δ = 10.10 (s, 1H), 9.14 (d, J = 2.2 Hz, 1H), 8.61 (dd, J = 2.4, 8.7 Hz, 1H), 8.33 (s, 1H), 8.03 - 7.88 (m, 2H), 7.71 (d, J = 8.2 Hz, 1H), 4.06 (s, 3H), 1.50 (s, 9H) Step 2: To a screw-cap vial equipped with a magnetic stir bar was added tert-butyl N- [5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]carbamate (430 mg, 1.06 mmol, 1 eq) and HCl/dioxane (2 M, 10 mL) sequentially. The vial was sealed with a teflon-lined septum. Then the mixture was stirred at 60 °C for 2 hours. LC-MS showed reactant remained. HCl/dioxane (2 M, 15 mL) was added and the mixture was stirred at 60 °C for 2 hours. The reaction mixture was concentrated in vacuum to give product 5-(4-chloro-6-fluoro-7- methoxy-2-quinolyl) pyridin-2-amine (390 mg, HCl salt) as yellow solid. Step 3: To a screw-cap vial equipped with a magnetic stir bar was added 2-(tert- butoxycarbonylamino) -2-methyl-propanoic acid (200 mg, 984 μmol, 1.5 eq) and DCE (5 mL) and ethyl 2-ethoxy-2H-quinoline-1-carboxylate (350 mg, 1.42 mmol, 2.1 eq) and 5-(4- chloro-6-fluoro-7-methoxy-2-quinolyl) pyridin-2-amine (200 mg, 658 μmol, 1 eq) and DIPEA (300 mg, 2.32 mmol, 3.5 eq) sequentially. The vial was sealed with a teflon-lined septum. Then the mixture was stirred at 80 °C for 16 hours. LC-MS showed 45% of reactant amine remained. 2-(tert-butoxycarbonylamino)-2-methyl-propanoic acid (200 mg, 984 μmol, 1.5 eq) and ethyl 2-ethoxy-2H-quinoline-1-carboxylate (300 mg, 1.21 mmol, 1.8 eq) was added the mixture was stirred at 80°C for 5 hours. LC-MS showed not complete. 2-(tert- butoxycarbonylamino) -2-methyl-propanoic acid (200 mg, 984 μmol, 1.5 eq) and ethyl 2- ethoxy-2H-quinoline-1-carboxylate (300 mg, 1.21 mmol, 1.8 eq) was added and the mixture was stirred at 80°C for 16 hours. The reaction was diluted with DCM (20 mL) and water (20 Attorney Docket No.: 185992002240 mL) and then the resulting organic phase was extracted with DCM (10 mL, 3 times). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (Biotage, 100-200 mesh silica gel, product came out at B=40%. A: Petroleum ether, B: Ethyl acetate) to afford C.1ai (100 mg, 204 μmol, 31% yield) as yellow gum. C.1aj: tert-butyl N-[2-[4-[4-chloro-7-(dimethylamino)-2-quinolyl]phenoxy]ethyl]-N-methyl- carbamate
Figure imgf000297_0001
According to Scheme 3 Step 1: A solution of 2,4-dichloro-N,N-dimethyl-quinolin-7- amine (200 mg, 829.48 μmol, 1 eq) and tert-butyl N-methyl-N-[2-[4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate (312.95 mg, 829.48 μmol, 1 eq) in S1 (6.6 mL). After work-up C.1aj (0.3 g, crude) was obtained as a yellow solid. MS m/z (ESI) [M+H]+= 456.1. C.1ak: tert-butyl N-[2- (7-bromo-4-chloro-2-quinolyl)-2-pyridyl]oxy]ethyl]-N-methyl-
Figure imgf000297_0002
carbamate
Figure imgf000297_0003
According to Scheme 3 Step 1: A mixture of 7-bromo-2,4-dichloro-quinoline (500 mg, 1.81 mmol, 1 eq) , tert-butyl N-methyl-N-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-2-pyridyl]oxy]ethyl]carbamate (615 mg, 1.63 mmol, 9.01e-1 eq) in S2 (6.6 mL). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethylacetate/Petroleum ether gradient @ 50 mL/min) to give C.1ak (650 mg, 1.12 mmol, 62.10% yield, 85% purity). MS m/z (ESI) [M+H]+= 494.0. Attorney Docket No.: 185992002240 C.1al: afford tert-butyl N-[2- [4-chloro-7-(dimethylamino)-2-quinolyl]-3-
Figure imgf000298_0001
pyridyl]oxy]ethyl]-N-methyl-carbamate
Figure imgf000298_0002
Step 1: To a solution of 6-bromopyridin-3-ol (17 g, 97.70 mmol, 1 eq), PPh3 (28.19 g, 107.47 mmol, 1.1 eq) and tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (20.54 g, 117.24 mmol, 1.2 eq) in THF (170 mL) was added DIAD (21.73 g, 107.47 mmol, 20.84 mL, 1.1 eq) at 0 °C under N2. The reaction solution was stirred at 25 °C for 12 hours. The reaction mixture was partitioned between EtOAc (1000 mL) and water (500 mL), washed with brine(400 mL), died over Na2SO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography (ISCO; 330 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give the tert-butyl N-[2-[(6- bromo-3-pyridyl)oxy]ethyl]-N-methyl-carbamate (6 g, 18.12 mmol, 18.54% yield) as a white solid. 1H NMR (400 MHz, CDCl3) d (ppm): 8.05 (d, J = 3.0 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.10 (br d, J = 6.4 Hz, 1H), 4.15 - 4.07 (m, 2H), 3.61 (br t, J = 5.4 Hz, 2H), 2.97 (s, 3H), 1.46 (s, 9H). Step 2: To a solution of tert-butyl N-[2-[(6-bromo-3-pyridyl)oxy]ethyl]-N-methyl- carbamate (4.3 g, 12.98 mmol, 1 eq), Pd2(dba)3 (1.2 g, 1.31 mmol, 1.01e-1 eq), PCy3 (0.75 g, 2.67 mmol, 867.05 μL, 2.06e-1 eq) and LiCl (2.79 g, 65.93 mmol, 1.35 mL, 5.08 eq) in dioxane (40 mL) was added tributyl(tributylstannyl)stannane (22.03 g, 37.98 mmol, 19.02 mL, 2.93 eq) under N2. The reaction solution was stirred at 110 °C for 12 hours. The reaction solution was extracted with EtOAc (200 mL, 3 times). The combined organic phase was washed with brine (200 mL, 2 times), dried over Na2SO4, filtered and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~3% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; gradient: 90%-100% B over 15 Attorney Docket No.: 185992002240 min). After Prep-HPLC purification, the eluent was concentrated to give tert-butyl N-methyl- N-[2-[(6-tributylstannyl-3-pyridyl)oxy]ethyl]carbamate (5 g, 4.80 mmol, 36.99% yield, 91% purity) as a colorless oil. MS m/z (ESI) [M+H]+= 543.3. Step 3: To a solution of tert-butyl N-methyl-N-[2-[(6-tributylstannyl-3- pyridyl)oxy]ethyl]carbamate (1 g, 1.85 mmol, 1 eq) , 2,4-dichloro-N,N-dimethyl-quinolin-7- amine (600 mg, 2.49 mmol, 1.35 eq) and LiCl (420 mg, 9.91 mmol, 203.09 μL, 5.36 eq) in m- xylene (20 mL) was added Pd(PPh3)2Cl2 (260 mg, 370.43 μmol, 2.01e-1 eq) under N2. The reaction solution stirred at 130 °C for 12 hours. The reaction solution was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to C.1al (450 mg, 807.50 μmol, 43.71% yield, 82% purity) as a yellow oil. MS m/z (ESI) [M+H]+= 457.2. C.1am: tert-butylN-[2- (7-bromo-4-chloro-2-quinolyl)-3-pyridyl]oxy]ethyl]-N-methyl-
Figure imgf000299_0001
carbamate
Figure imgf000299_0002
According to Scheme 3 Step 1: A mixture of 7-bromo-2,4-dichloro-quinoline (500 mg, 1.81 mmol, 1 eq), tert-butyl N-methyl-N-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-2-pyridyl]oxy]ethyl]carbamate (615 mg, 1.63 mmol, 9.01e-1 eq) in S2 (6.6 mL). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethylacetate/Petroleum ether gradient @ 50 mL/min) to give C.1am (650 mg, 1.12 mmol, 62.10% yield, 85% purity). MS m/z (ESI) [M+H]+= 494.0. C.1an: tert-butyl N-[2- chloro-7-(dimethylamino)-6-fluoro-2-quinolyl]-2-
Figure imgf000299_0003
pyridyl]oxy]ethyl]-N-methyl-carbamate
Figure imgf000299_0004
According to Scheme 3 Step 1: A mixture of 2,4-dichloro-6-fluoro-N,N-dimethyl- quinolin-7-amine (500 mg, 1.93 mmol, 1 eq), tert-butyl N-methyl-N-[2-[[5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]ethyl]carbamate (730 mg, 1.93 mmol, 1 eq) in S2 (11 mL). After work-up the residue was purified by flash silica gel chromatography Attorney Docket No.: 185992002240 (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.1an (800 mg, 1.68 mmol, 87.29% yield, 100% purity) as yellow oil. MS m/z (ESI) [M+H]+= 475.1. C.1ao: tert-butyl N-[2- chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]-methyl-
Figure imgf000300_0001
amino]ethyl]-N-methyl-carbamate
Figure imgf000300_0002
According to Scheme 3 Step 1: A mixture of 2,4-dichloro-6-fluoro-7-methoxy- quinoline (0.200 g, 0.813 mmol, 1.00 eq) ,tert-butyl N-methyl-N-[2-[methyl-[5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl] amino]ethyl]carbamate (318 mg, 0.813 mmol, 1.00 eq) in S2 (4.5 mL). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.1ao (350 mg, 0.538 mmol, 66.2% yield, 73% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 475.3. C.1ap: tert-butyl 3-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl) phenoxy]azetidine-1- carboxylate
Figure imgf000300_0003
According to Scheme 3 Step 1: A solution of 2, 4-dichloro-6-fluoro-7-methoxy- quinoline (200 mg, 813 μmol, 1.00 eq), tert-butyl 3-[4-(4, 4, 5, 5-tetramethyl-1, 3, 2- dioxaborolan-2-yl) phenoxy]azetidine-1-carboxylate (305 mg, 813 μmol, 1.00 eq) in S2 (4.4 mL). After work-up the residue was purified by prep-TLC (SiO2, PE: EtOAc = 3:1) to give C.1ap (230 mg, 501 μmol, 61.7% yield) as yellow oil. MS m/z (ESI) [M+H]+= 459.1. C.1aq: tert-butyl 3-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl) phenoxy]pyrrolidine-1- carboxylate
Figure imgf000300_0004
According to Scheme 3 Step 1: A solution of 2, 4-dichloro-6-fluoro-7-methoxy- quinoline (200 mg, 813 μmol, 1.00 eq), tert-butyl 3-[4-(4, 4, 5, 5-tetramethyl-1, 3, 2- Attorney Docket No.: 185992002240 dioxaborolan-2-yl) phenoxy]pyrrolidine-1-carboxylate (316.4 mg, 813 μmol, 1.00 eq) in S2 (4.4 mL). After work-up the residue was purified by prep-TLC (SiO2, PE: EtOAc = 3:1) to give C.1aq (260 mg, 550 μmol, 67.6% yield) as yellow oil. MS m/z (ESI) [M+H]+= 473.3. C.1ar: tert-butyl 3-[[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2- pyridyl]oxymethyl]azetidine-1-carboxylate
Figure imgf000301_0001
According to Scheme 3 Step 1: A solution of 2,4-dichloro-6-fluoro-7-methoxy- quinoline (0.3 g, 1.22 mmol, 1 eq) , tert-butyl 3-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate (475.83 mg, 1.22 mmol, 1 eq) in S2 (11 mL). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~15%Ethylacetate/Petroleum ether gradient @ 45 mL/min) to give C.1ar (400 mg, 759.62 μmol, 62.30% yield, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 474.2. C.1as: tert-butyl N-[2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenyl]sulfanylethyl]-N- methyl-carbamate
Figure imgf000301_0002
According to Scheme 3 Step 1: A mixture of tert-butyl N-methyl-N-[2-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfanylethyl]carbamate (320 mg, 813.53 μmol, 1 eq), 2,4-dichloro-6-fluoro-7-methoxy-quinoline (200 mg, 812.79 μmol, 1 eq) in S2 (5.5 mL). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~15% Ethyl acetate/Petroleum ether gradient @ 18 mL/min) to give C.1as (250 mg, 486.91 μmol, 59.91% yield, 92.9% purity) as colorless oil. MS m/z (ESI) [M+H]+= 477.1. C.1at: 2- [4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]imidazol-1- yl]methoxy]ethyl-trimethyl-silane
Figure imgf000301_0003
Attorney Docket No.: 185992002240 According to Scheme 3 Step 1: A solution of 2,4-dichloro-6-fluoro-7-methoxy- quinoline (350 mg, 1.42 mmol, 1 eq), trimethyl-[2-[[4-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenoxy]imidazol-1-yl]methoxy]ethyl]silane (550 mg, 1.32 mmol, 9.29e-1 eq) ) in S2 (4.5 mL). After work-up the crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.1at (450 mg, 818.94 μmol, 57.58% yield, 91% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 500.1. C.1au: tert-butyl N-[2-[4-[4-chloro-7-(dimethylamino)-6-fluoro-2-quinolyl]phenoxy]ethyl]- N-methyl-carbamate
Figure imgf000302_0001
According to Scheme 3 Step 1: A solution of 2,4-dichloro-6-fluoro-N,N-dimethyl- quinolin-7-amine (150 mg, 578.91 μmol, 1 eq) , tert-butyl N-methyl-N-[2-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate (218.41 mg, 578.91 μmol, 1 eq) in S1 (4.4 mL). After work-up the residue was purified by prep-TLC (Petroleum ether : Ethyl acetate=3:1) to give C.1au (0.2 g, 379.77 μmol, 65.60% yield, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 474.2. C.1av: tert-butyl N-[2- [4-chloro-6-fluoro-7-(trideuteriomethoxy)-2-quinolyl]-3-
Figure imgf000302_0002
pyridyl]oxy]ethyl]-N-methyl-carbamate
Figure imgf000302_0003
According to Scheme 3 Step 1: To a solution of 2,4-dichloro-6-fluoro-7- (trideuteriomethoxy)quinoline (260 mg, 1.04 mmol, 1 eq) in o-xylene (10 mL) was added tert-butyl N-methyl-N-[2-[(6-tributylstannyl-3-pyridyl)oxy]ethyl]carbamate (650.00 mg, 1.20 mmol, 1.15 eq) , LiCl (195.00 mg, 4.60 mmol, 94.29 μL, 4.41 eq), PdCl2(PPh3)2 (195.00 mg, 277.82 μmol, 2.66e-1 eq), then the resulting mixture was purged with N2 three times and stirred at 100°C for 12 hours. The reaction mixture was partitioned between EtOAc (60 mL) and water (30 mL), washed with brine(30 mL), died over Na2SO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) Attorney Docket No.: 185992002240 to give C.1av (450 mg, 967.88 μmol, 92.72% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) d (ppm): 8.55 - 8.48 (m, 2H), 8.40 (d, J = 2.9 Hz, 1H), 7.86 (d, J = 11.6 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 2.6, 8.6 Hz, 1H), 4.24 (br d, J = 2.3 Hz, 2H), 3.74 - 3.60 (m, 2H), 3.03 (s, 3H), 1.49 (s, 9H). C.1aw: tert-butyl 3- (4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]methyl]azetidine-
Figure imgf000303_0001
1-carboxylate
Figure imgf000303_0002
According to Scheme 3 Step 1: A solution of 2,4-dichloro-6-fluoro-7-methoxy- quinoline (500 mg, 2.03 mmol, 1 eq), tert-butyl 3-[[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenoxy]methyl]azetidine-1-carboxylate (790 mg, 2.03 mmol, 9.99e-1 eq) in S1 (7 mL).After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~40% PE:EtOAc gradient @ 40 mL/min) to afford C.1aw (500 mg, 919.79 μmol, 45.27% yield, 87% purity) as a yellow oil. MS (ESI) m/z [M+H]+= 473.2. C.1ax: tert-butyl (2-(4-(7-ethoxy-4-(4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin- 2-yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000303_0003
Step1: To a solution of 2,4-dichloro-7-methoxy-quinoline (7 g, 30.69 mmol, 1 eq) in DCM (100 mL) was added BBr3 (2 M, 46 mL, 3 eq) at 0°C under N2 and stirred at 0°C for 2 hours. The reaction solution was quenched by H2O (200 mL). The mixture was extracted with ethyl acetate (300 mL, 2 times). The combined organic phases were washed with brine (300 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 20/1) to give 2,4- dichloroquinolin-7-ol (5 g, 22.89 mmol, 74.59% yield, 98% purity) as a white solid. MS m/z (ESI) [M+H]+= 241.1. Step 2: According to Scheme 3 Step 1: A solution of 2,4-dichloroquinolin-7-ol (1.3 g, 6.07 mmol, 1 eq), tert-butyl N-methyl-N-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]ethyl]carbamate (1.46 g, 3.88 mmol, 6.38e-1 eq) in S1 (11 mL). After work-up Attorney Docket No.: 185992002240 the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% DCM/MeOH gradient @ 40 mL/min) to afford tert-butyl N- [2-[4-(4-chloro-7-hydroxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (760 mg, 1.20 mmol, 19.84% yield, 68% purity) as a yellow oil. MS m/z (ESI) [M+H]+= 429.2. Step 3: To a solution of tert-butyl N-[2-[4-(4-chloro-7-hydroxy-2-quinolyl) phenoxy]ethyl]-N-methyl-carbamate (250 mg, 582.88 μmol, 1 eq) in MeCN (5 mL) was added iodoethane (130 mg, 833.52 μmol, 66.67 μL, 1.43 eq) and K2CO3 (240 mg, 1.74 mmol, 2.98 eq). The reaction mixture was stirred at 60 °C for 12 hours. The residue was partitioned between ethyl acetate (10 mL) and water (20mL). The aqueous layer was extracted with ethyl acetate (20mL, 2 times). The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 20~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to afford C.1ax (180 mg, 393.91 μmol, 67.58% yield, 100% purity) as yellow oil. MS m/z (ESI) [M+H]+= 457.3. C.1ay: tert-butyl N-[2-[4-(4-chloro-8-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N- methyl-carbamate
Figure imgf000304_0001
According to Scheme 3 Step1: A solution of 2,4-dichloro-8-fluoro-7-methoxy- quinoline (300 mg, 1.22 mmol, 1 eq) in toluene (3mL) and tert-butyl N-methyl-N-[2-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy]ethyl]carbamate (450 mg, 1.19 mmol, 9.78e-1 eq) in S2 (6.6 mL). After work-up the crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.1ay (120 mg, 260.35 μmol, 21.35% yield, 100% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 461.2. C.1az: 1-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]pyrrolidin-2-one
Figure imgf000304_0002
To a solution of tert-butyl N-[2-[4-(4-chloro-7-hydroxy-2-quinolyl) phenoxy]ethyl]-N- methyl-carbamate (250 mg, 582.88 μmol, 1 eq) in MeCN (5 mL) was added trideuterio (iodo) methane (120 mg, 827.83 μmol, 51.52 μL, 1.42 eq) and K2CO3 (240 mg, 1.74 mmol, 2.98 eq). Attorney Docket No.: 185992002240 The reaction mixture was stirred at 60°C for 12 hours. The residue was partitioned between EtOAc (10 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (20mL, 2 times). The combined organic layers were dried over (Na2SO4) and evaporated to give a crude material which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 20~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to afford C.1az (200 mg, 448.48 μmol, 76.94% yield, 100% purity) as yellow oil. MS m/z (ESI) [M+H]+= 446.2. General procedures for Buchwald coupling and SNAr reactions: Intermediates B.1 (Scheme 2; Step 1), C.2 (Scheme 3; Step 2), D.1 (Scheme 5; Step 1), E.1 (Scheme 6; Step 1) Conditions 1 Buchwald. A mixture of derivative A.4, A.5 or C.1 (1.0 eq), amine (2.0 eq), BrettPhos Pd G3 (0.10 eq), t-BuONa (3.0 eq) in dioxane (0.10 M) was degassed and purged with N2 three times at 25 °C, and then the mixture was stirred at 80 °C for 16 hours under N2 atmosphere. The mixture was diluted with water and extracted with EtOAc (3 times). The combine organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue. Conditions 2 Buchwald. A mixture of derivative A.4, A.5 or C.1 (1.0 eq), amine (1.3 eq), PdP(t-Bu)3 (0.10 eq), t-BuONa (3.0 eq) in dioxane (0.15 M) was degassed and purged with N2 three times at 25 °C, and then the mixture was stirred at 80 °C for 16 hours under N2 atmosphere. The mixture was diluted with water and extracted with EtOAc (3 times). The combine organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue. Conditions 3 Buchwald. A mixture of derivative A.4, A.5 or C.1 (1.0 eq), amine (3.0 eq), CPhos Pd G3 (0.10 eq), CsCO3 (2.0 eq) in dioxane (0.10 M) was degassed and purged with N2 three times at 25 °C, and then the mixture was stirred at 80 °C for 16 hours under N2 atmosphere. The mixture was diluted with water and extracted with EtOAc (3 times). The combine organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue. Conditions 4 Buchwald. A mixture of derivative A.4, A.5 or C.1 (1.0 eq), amine (1.2 eq), SPhos Pd G3 (0.10 eq), Cs2CO3 (3.0 eq) in dioxane was degassed and purged with N2 for three times, and then the mixture was stirred at 80 °C for 16 hours under N2 atmosphere. The mixture was diluted with water and extracted with ethyl acetate (3 times). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. Attorney Docket No.: 185992002240 Conditions 1 SNAr: To a solution of quinoline A.4, A.5 or C.1 (1.0 eq), amine (1.5 eq) in dimethyl sulfoxide (0.40 M) was added cesium fluoride (2.0 eq) at 25 °C. After stirring at 130 °C for 16 hours, the reaction mixture was added into water (0.08 M) and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine (three times), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Conditions 2 SNAr: To a screw-cap vial equipped with a magnetic stir bar was added A.4, A.5 or C.1 (1.0 eq), and amine (> 10 eq) sequentially. The vial was sealed with a Teflon-lined septum. Then the mixture was stirred at 130 °C for 16 h. The reaction mixture was diluted with EtOAc and water, and then the resulting organic phase was extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuum to give the product. Conditions 3 SNAr: To a solution of A.4, A.5 or C.1 (1.0 eq) in DMSO (0.40 M) was added amine (3.0 eq) and DIEA (1.7 eq) at 25 °C. The mixture was stirred at 100 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. B.1a: tert-butyl 2-(2-chloro-7-methoxyquinolin-4-yl)-2,7-diazaspiro [4.5] decane-7- carboxylate
Figure imgf000306_0001
According to Scheme 2 Step 1: Conditions 3 SNAr: To 2,4-Dichloro-7- methoxyquinoline (0.38 g, 1.7 mmol, 1.0 eq) in DMSO (1.7 M) was added DIEA and amine (1.5 eq). After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 25%- 55% over 15 min). The eluent was lyophilized to give B.1a (0.33 g, 0.76 mmol, 46% yield, 100% purity) as a yellow solid. Attorney Docket No.: 185992002240 B.1b: 2-(2-chloro-7-methoxyquinolin-4-yl)-7-methyl-2,7-diazaspiro [4.5] decane
Figure imgf000307_0001
To a solution B.1a (0.28 g, 0.64 mmol, 1.0 eq) in THF (4.0 mL) was added LiAlH4 (2.5 M, 1.0 mL, 3.9 eq) at 0 °C under N2 atmosphere. The reaction mixture was stirred at 25 °C for 10 min, then the mixture was stirred at 50 °C for 2 h. To the reaction mixture was added THF (20 mL) to dilute the reaction solution, then to the mixture was added Na2SO4. To the reaction mixture was added H2O dropwise until there was no air bubble in the reaction system. Then the reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue obtained was purified by prep-TLC (SiO2, PE/EtOAc = 1:1) to give B.1b (80 mg, 0.22 mmol, 35% yield, 95% purity) as a colorless gum. C.2a: tert-butyl 4-(4-(4-morpholinoquinolin-2-yl)phenyl)piperazine-1-carboxylate
Figure imgf000307_0002
According to Scheme 3 Step 2: Conditions 1 Buchwald with C.1b (0.20 g, 0.47 mmol, 1.0 eq). After work-up the residue was purified by Flash chromatography (40 g column, Eluent of 0-21% EtOAc/PE gradient at 40 mL/min) to give C.2a (0.65 g, 1.5 mmol, 87% yield) as a yellow solid. MS m/z (ESI) [M+H]+= 475.3. C.2b: tert-butyl N-[5-[6-fluoro-4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2- quinolyl]-2-pyridyl]-N-methylcarbamate
Figure imgf000307_0003
According to Scheme 3 Step 2: Conditions 1 Buchwald with C.1k (0.15 g, 0.36 mmol, 1.0 eq). After work-up the residue obtained was purified by Flash chromatography (12 Attorney Docket No.: 185992002240 g column, eluent of 0~20% EtOAc/PE gradient at 40 mL/min) to afford C.2b (40 mg, 43 μmol, 12% yield, 52% purity) as a light-yellow oil. MS m/z (ESI) [M+H]+= 483.2. C.2c: tert-butyl N-cyclopropyl-N-[2-[[5-[6-fluoro-4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7- methoxy -2-quinolyl]-2-pyridyl] oxy] ethyl] carbamate
Figure imgf000308_0001
According to Scheme 3 Step 2: Conditions 4 Buchwald with C.1n (0.12 g, 0.17 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-TLC (petroleum ether: ethyl acetate = 0:1) to give C.2c (50 mg, 0.06 mmol, 35% yield, 65% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 553.3. C.2d: tert-butyl N-[2-[5-[6-fluoro-4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2- quinolyl]-2-pyridyl]-1-methyl-2-oxo-ethyl] carbamate
Figure imgf000308_0002
According to Scheme 3 Step 2: Conditions 4 Buchwald with C.1o (0.24 g, 0.52 mmol, 1.0 eq). After work-up the residue obtained was purified by Flash chromatography (20 g column, Eluent of 0~75% EtOAc/PE gradient at 60 mL/min) to give C.2d (0.16 g, 0.28 mmol, 53% yield, 91% purity) as an orange solid. C.2e: tert-butyl 4- [5-(6, 7-dimethoxy-4-pyrrolidin-1-yl-2-quinolyl)-2-pyridyl] piperazine-1- carboxylate
Figure imgf000308_0003
According to Scheme 3 Step 2: Conditions 2 SNAr with C.1c (0.45 g, 0.93 mmol, 1.0 eq) and pyrrolidine (54 eq). After work-up C.2e (0.50 mg, crude) was obtained as brown oil. Attorney Docket No.: 185992002240 C.2f: tert-butyl-[2-[4-[5-(6,7-dimethoxy-4-pyrrolidin-1-yl-2-quinolyl)-2-pyridyl] piperazin- 1-yl] ethoxy]-dimethyl-silane
Figure imgf000309_0001
According to Scheme 3 Step 2: Conditions 3 SNAr with C.1u (0.12 g, 0.22 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 20%-50% over 10 min) to give C.2f (80 mg, 0.12 mmol, 56% yield, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 578.4. C.2g: tert-butyl 4-[5-[4-(3-hydroxy-3-methyl-pyrrolidin-1-yl)-7-methoxy-2-quinolyl]-2- pyridyl] piperazine-1-carboxylate
Figure imgf000309_0002
According to Scheme 3 Step 2: Conditions 3 SNAr with C.1e (100 mg, 219.81 μmol, 1 eq). After work-up the crude product was used in the next step without purification. C.2g (0.10 g, 0.17 mmol, 77% yield, 88% purity) was obtained as a white solid. MS m/z (ESI) [M+H]+= 502.5. C.2h: tert-butyl 4-[5-[4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2-quinolyl]-2- pyridyl] piperazine-1-carboxylate
Figure imgf000309_0003
According to Scheme 3 Step 2: Conditions 3 SNAr with C.1e (0.20 g, 0.31 mmol, 1.0 eq). After work-up the crude product was used in the next step without purification. C.2h (0.15 g, 0.25 mmol, 81% yield, 86% purity) was obtained as a white solid. MS m/z (ESI) [M+H]+= 520.3. Attorney Docket No.: 185992002240 C.2i: tert-butyl 4-[4-[7-methoxy-4-(3-methoxypyrrolidin-1-yl) -2-quinolyl] phenyl] piperazine-1-carboxylate
Figure imgf000310_0001
According to Scheme 3 Step 2: Conditions 3 SNAr with C.1f (0.55 g, 1.2 mmol, 1.0 eq). After work-up C.2i (0.55 g, crude) was obtained as a white solid. MS m/z (ESI) [M+H]+= 519.3. C.2j: tert-butyl N-[2-[4-[7-(dimethylamino)-6-methoxy-4-(3-methoxypyrrolidin-1-yl)-2- quinolyl] phenoxy] ethyl]-N-methylcarbamate
Figure imgf000310_0002
According to Scheme 3 Step 2: Conditions 2 SNAr with C.1h (0.14 g, 0.29 mmol, 1.0 eq and 3-methoxypyrrolidine (10 eq). After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 30%-60% over 10 min) to give C.2j (0.10 g, 0.18 mmol, 63% yield, 100% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 511.4. C.2k: tert-butyl 4-[5-[7-(dimethylamino)-4-(3-methoxypyrrolidin-1-yl)-2-quinolyl]-2- pyridyl] piperazine-1-carboxylate
Figure imgf000310_0003
According to Scheme 3 Step 2: Conditions 2 SNAr with C.1i (0.50 g, 1.1 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 27%-47% B over 10 min) to give C.2k (0.3 g, 0.54 mmol, 50% yield, 95% purity) as a yellow solid. MS m/z (ESI) [M+H]+ =533.3. Attorney Docket No.: 185992002240 C.2l: tert-butyl N-[2-[[5-[7-(dimethylamino)-4-(3-methoxypyrrolidin-1-yl)-2-quinolyl]-2- pyridyl] oxy] ethyl] -N-methylcarbamate
Figure imgf000311_0001
According to Scheme 3 Step 2: Conditions 2 SNAr with tert-butyl N-[2-[[5-[4-chloro- 7-(dimethylamino)-2-quinolyl]-2-pyridyl] oxy] ethyl]-N-methyl-carbamate C.1j (0.80 g, 1.1 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 23%-53% over 15 min) to give C.2l (0.20 g, 0.36 mmol, 35% yield, 95% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 522.3. C.2m: tert-butyl 4-[5-[4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2-quinolyl]-2- pyridyl] piperazine-1-carboxylate
Figure imgf000311_0002
According to Scheme 3 Step 2: Conditions 3 SNAr with C.1e (0.57 g, 1.3 mmol, 1.0 eq). After work-up C.2m (0.70 g, 1.2 mmol, 96% yield, 89% purity) was obtained as a yellow oil. MS m/z (ESI) [M+H]+=520.3. C.2n: tert-butyl 4-[5-[4-[3-(hydroxymethyl) pyrrolidin-1-yl]-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate
Figure imgf000311_0003
According to Scheme 3 Step 2: Conditions 3 SNAr with C.1a (0.20 g, 0.47 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-TLC (SiO2, DCM/MeOH = 10:1) to give C.2n (0.15 g, 291.05 μmol, 61.84% yield, 95% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 490.2. Attorney Docket No.: 185992002240 C.2o: tert-butyl 4-(5-(4-(2-methylpyrrolidin-1-yl) quinolin-2-yl) pyridin-2-yl) piperazine-1- carboxylate
Figure imgf000312_0001
According to Scheme 3 Step 2: Conditions 2 SNAr with C.1a (0.15 g, 0.35 mmol, 1.0 eq), 2-methylpyrrolidine (30 eq). The reaction mixture was evaporated under vacuo and purification was done by flash chromatography (DCM/MeOH: 0% to 10%) to give C.2o (0.16 g, 0.27 mmol, 75%). C.2p: tert-butyl 4-(5-(4-(pyrrolidin-1-yl) quinolin-2-yl) pyridin-2-yl) piperazine-1- carboxylate
Figure imgf000312_0002
According to Scheme 3 Step 2: Conditions 2 SNAr with C.1a (0.15 g, 0.35 mmol, 1.0 eq), pyrrolidine (30 eq). At 90 °C. The reaction mixture was evaporated in vacuo and purified by flash chromatography (DCM/MeOH 0% to 10%) to give C.2p (0.16 g, 0.35 mmol, 98%). C.2q: tert-butyl 4-(5-(7-methoxy-4-(7-methyl-2,7-diazaspiro [4.5] decan-2-yl) quinolin-2-yl) pyridin-2-yl) piperazine-1-carboxylate
Figure imgf000312_0003
According to Scheme 4 Step 1: To a solution of B.1b (80 mg, 0.23 mmol, 1.0 eq) and tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine-1- carboxylate (0.11 g, 0.28 mmol, 1.0 eq) in S2 (1.35 mL) was added Pd(PPh3)4 (0.10 eq), sodium carbonate (2.0 eq). After work-up the residue was purified by Flash chromatography (12 g column, Eluent of 0 to 30% EtOAc/PE gradient at 40 mL/min) then by prep-TLC (SiO2, PE/EtOAc = 1:1) to give C.2q (0.10 g, 0.16 mmol, 68% yield, 90% purity) as a colourless gum. Attorney Docket No.: 185992002240 C.2r: tert-butyl 4-[4-(4-pyrrolidin-1-yl-2-quinolyl) phenyl] piperazine-1-carboxylate
Figure imgf000313_0001
According to Scheme 3 Step 2: Conditions 2 Buchwald: C.1b (0.30 g, 0.57 mmol, 1.0 eq, 80% purity) and pyrrolidine (48 mg, 0.68 mmol, 57 mL, 1.2 eq) were stirred in dioxane (5.0 mL) at 100 °C for 16 hours. The mixture was concentrated to give a residue. The crude product was used in the next step without purification. C.2r (0.30 g, 0.46 mmol, 81% yield, 70% purity) was obtained as a yellow solid. MS m/z (ESI) [M+H]+=459.4. C.2s: tert-butyl 4-(5-(6-acetamido-4-(3-(hydroxymethyl) pyrrolidin-1-yl)-7- methoxyquinolin-2-yl) pyridin-2-yl) piperazine-1-carboxylate
Figure imgf000313_0002
According to Scheme 3 Step 2: To a solution of C.1w (0.32 g, 0.54 mmol, 1.0 eq) in DMSO (3.0 mL) were added pyrrolidin-3-ylmethanol (0.11 g, 1.1 mmol, 2.0 eq) and N, N- diisopropylethylamine (0.28 g, 2.2 mmol, 4.0 eq) at 20 °C. The mixture was stirred at 100 °C for 16 hours and then concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (4 g column, EtOAc/PE gradient at 40 mL/min) to give tert-butyl 4-[5-[6-bromo-4-[3- (hydroxymethyl)pyrrolidin-1-yl]-7-methoxy-2-quinolyl]-2- pyridyl]piperazine-1-carboxylate (0.30 g, 0.49 mmol, 91% yield, 98% purity) as a yellow solid. MS m/z (ESI) [M+H]+=600.2. To a mixture of tert-butyl 4-[5-[6-bromo-4-[3-(hydroxymethyl)pyrrolidin-1-yl]-7- methoxy -2-quinolyl]-2-pyridyl]piperazine-1-carboxylate (0.28 g, 0.47 mmol, 1.0 eq) and acetamide (55 mg, 0.94 mmol, 2.0 eq) in dioxane (3.0 mL) were added Xantphos-Pd G4 (45 mg, 0.05 mmol, 0.10 eq) and CsCO3 (0.31 g, 0.94 mmol, 2.0 eq) at 20 °C. The mixture was stirred at 100 °C for 6 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (10 mL), then the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (12 g column, Attorney Docket No.: 185992002240 Eluent of 0% to 5% MeOH/EtOAc gradient at 30 mL/min) to give C.2s (0.20 g, 0.29 mmol, 62% yield, 83% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 577.3. C.2t: tert-butyl 2-(4-(5-(4-(3-(hydroxymethyl) pyrrolidin-1-yl)-7-methoxyquinolin-2-yl) pyridin-2-yl) piperazine-1-carbonyl) pyrrolidine-1-carboxylate
Figure imgf000314_0001
To a solution of Example 10 (0.15 g, 0.36 mmol, 1.0 eq) in DMF (2.0 mL) was added HATU (0.21 g, 0.54 mmol, 1.5 eq), 1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (90 mg, 0.42 mmol, 1.2 eq) and DIEA (0.14 g, 1.1 mmol, 0.19 mL, 3.0 eq) at 25 °C. The mixture was stirred at 25 °C for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL, three times). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, PE/EtOAc = 0:1) to give C.2t (0.12 g, 0.14 mmol, 38% yield, 70% purity) as yellow gum. MS m/z (ESI) [M+H]+= 617.3. C.2u: tert-butyl 4-(5-(7-methoxy-4-(2-oxa-6-azaspiro[3.4]octan-6-yl)quinolin-2-yl)pyridin-2- yl)piperazine-1-carboxylate
Figure imgf000314_0002
According to Scheme 3 Step 2: To a solution of tert-butyl 4-[5-(4-chloro-7-methoxy- 2-quinolyl)-2-pyridyl] piperazine-1-carboxylate (0.25 g, 0.54 mmol, 1.0 eq) in DMSO (3.0 mL) were added 2-oxa-6-azaspiro[3.4]octane (0.12 g, 1.1 mmol, 2.0 eq) and N, N- diisopropylethylamine (0.28 g, 2.2 mmol, 4.0 eq) at 25 °C. The mixture was stirred at 100 °C for 16 hours then the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by Flash chromatography (4 g column, EtOAc/PE gradient at 40 mL/min) to give C.2u (0.27 g, 0.50 mmol, 91% yield, 98% purity). Attorney Docket No.: 185992002240 C.2v: tert-butyl 4-[5-[7-(dimethylamino)-4-[3-(hydroxymethyl)pyrrolidin-1-yl]-2-quinolyl]- 2-pyridyl]piperazine-1-carboxylate
Figure imgf000315_0001
According to Scheme 3 Step 2: To a solution of tert-butyl 4-[5-[4-chloro-7- (dimethylamino)-2-quinolyl]-2-pyridyl]piperazine-1-carboxylate (0.12 g, 256.42 μmol, 1 eq), pyrrolidin-3-ylmethanol (51.87 mg, 512.83 μmol, 2 eq) in DMSO (0.5 mL) was added CsF (116.85 mg, 769.25 μmol, 3 eq) at 25°C. After stirring at 130°C for 16 hours, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(FA)-ACN];gradient:20%-50% B over 10 min) to give C.2v (65 mg, 109.82 μmol, 42.83% yield, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 533.2. C.2w: tert-butyl N-[2-[4-[4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000315_0002
According to Scheme 3 Step 2: To a solution of tert-butyl N-[2-[4-(4-chloro-7- methoxy-2-quinolyl) phenoxy]ethyl]-N-methyl-carbamate (300 mg, 677.30 μmol, 1 eq) and DIEA (262.61 mg, 2.03 mmol, 353.92 μL, 3 eq) in DMSO (0.5 mL) was added pyrrolidin-3- ylmethanol (342.53 mg, 3.39 mmol, 5.0 eq) at 20 °C. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was quenched by addition of water (10 mL) at 20 °C, and then extracted with EtOAc (10 mL, 3 times). After work-up the crude C.2w (270 mg, 531.89 μmol, 78.53% yield) as yellow oil was used into the next step without further purification. Attorney Docket No.: 185992002240 C.2x: tert-butyl 4-[4-[4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2- quinolyl]phenyl]piperazine-1-carboxylate
Figure imgf000316_0001
According to Scheme 3 Step 2: To a solution of tert-butyl 4-[4-(4-chloro-7-methoxy- 2-quinolyl) phenyl]piperazine-1-carboxylate (400 mg, 722.53 μmol, 1 eq) in DMSO (3 mL) was added pyrrolidin-3-ylmethanol (200 mg, 1.98 mmol, 2.74 eq) and CsF (300 mg, 1.97 mmol, 2.73 eq) in turns, then the resulting mixture was stirred at 90 °C for 16 hours. The reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL, 2 times), brine (50 mL). After work-up the crude material was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 25 mL/min) to give C.2x (280 mg, 518.27 μmol, 71.73% yield, 96% purity) as yellow gum. MS m/z (ESI) [M+H]+= 519.3. C.2y: tert-butyl 4-[5-[7-(dimethylamino)-4-[3-(hydroxymethyl)pyrrolidin-1-yl]-2-quinolyl]- 2-pyridyl]piperazine-1-carboxylate
Figure imgf000316_0002
According to Scheme 3 Step 2: To a solution of tert-butyl 4-[5-(4-chloro-6-fluoro-7- methoxy-2-quinolyl) -2-pyridyl]piperazine-1-carboxylate (250 mg, 528.61 μmol, 1 eq) and pyrrolidin-3-ylmethanol (100 mg, 988.66 μmol, 1.87 eq) in dioxane (5 mL) was added SPhos Pd G3 (50 mg, 64.08 μmol, 1.21e-1 eq) and Cs2CO3 (400 mg, 1.23 mmol, 2.32 eq), then the resulting mixture was stirred at 80°C for 12 hours under N2. The reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL, 2 times), brine (50 mL). After work-up the crude material was purified by flash silica gel chromatography (ISCO®; 12 SepaFlash® Silica Flash Column, Eluent of 0~100 Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.2y (250 mg, 443.39 μmol, 83.88% yield, 95.35% purity) as colorless gum. MS m/z (ESI) [M+H]+= 538.3. Attorney Docket No.: 185992002240 C.2z: tert-butyl N-[2- (dimethylamino)-4-[3-(hydroxymethyl)pyrrolidin-1-yl]-2-
Figure imgf000317_0001
quinolyl]-2-pyridyl]oxy]ethyl]-N-methyl-carbamate
Figure imgf000317_0002
According to Scheme 3 Step 2: Conditions 1 SNAr: To a solution of tert-butyl N-[2- [[5-[4-chloro-7-(dimethylamino)-2-quinolyl]-2-pyridyl]oxy]ethyl]-N-methyl-carbamate (0.2 g, 437.67 μmol, 1 eq), pyrrolidin-3-ylmethanol (88.54 mg, 875.34 μmol, 2 eq) in DMSO (0.5 mL) was added CsF (99.73 mg, 656.51 μmol, 1.5 eq). After work-up the residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(FA)-ACN]; gradient:18%-48% B over 10 min) to give C.2z (130 mg, 249.21 μmol, 56.94% yield, 100% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 522.2. C.2aa: tert-butyl (2-((5-(7-(dimethylamino)-4-((cis)-5-methyloctahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate
Figure imgf000317_0003
According to Scheme 3 Step 2: Condition 4 Buchwald: A mixture of tert-butyl N-[2- [[5-[4-chloro-7-(dimethylamino)-2-quinolyl]-2-pyridyl]oxy]ethyl]-N-methyl-carbamate (300 mg, 656.51 μmol, 1 eq), cis 5-methyloctahydro-1H-pyrrolo[3,4-c]pyridine (110.47 mg, 787.81 μmol, 1.2 eq), Cs2CO3 (641.71 mg, 1.97 mmol, 3 eq) , SPhos Pd G3 (51.22 mg, 65.65 μmol, 0.1 eq) in dioxane (3 mL). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.2aa (200 mg, 356.68 μmol, 54.33% yield, 100% purity) as yellow oil. MS m/z (ESI) [M+H]+= 521.2. Attorney Docket No.: 185992002240 C.2ab: tert-butyl N-[2- (dimethylamino)-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-
Figure imgf000318_0001
2-quinolyl]-2-pyridyl]oxy]ethyl]-N-methyl-carbamate
Figure imgf000318_0002
According to Scheme 3 Step 2: Conditions 1 SNAr: To a solution of tert-butyl N-[2- [[5-[4-chloro-7-(dimethylamino)-2-quinolyl]-2-pyridyl]oxy]ethyl]-N-methyl-carbamate (300 mg, 656.51 μmol, 1 eq) , 2-methyl-2,6-diazaspiro[3.3]heptane (182.27 mg, 984.76 μmol, 1.5 eq, 2HCl) in DMSO (2 mL) was added CsF (498.63 mg, 3.28 mmol, 5 eq). After work-up the residue was purified by prep-HPLC (column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(FA)-ACN]; gradient:8%-38% B over 10 min) to give C.2ab (200 mg, 356.69 μmol, 54.33% yield, 95% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 533.3. C.2ac: tert-butyl N-[2-[4-[7-methoxy-4-(2-oxa-7-azaspiro[3.4]octan-7-yl) -2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000318_0003
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-7-methoxy-2-quinolyl) phenoxy]ethyl]-N-methyl-carbamate (270 mg, 609.57 μmol, 1 eq), 2-oxa-7-azaspiro[3.4]octane oxalate (106.06 mg, 670.53 μmol, 1.1 eq) and Cs2CO3 (397.22 mg, 1.22 mmol, 2.0 eq) in dioxane (2 mL) was added SPhos Pd G3 (47.56 mg, 60.96 μmol, 0.1 eq After work-up the residue was purified by prep-TLC (SiO2, DCM: MeOH = 10:1). C.2ac (240 mg, 461.87 μmol, 75.77% yield) was obtained as yellow oil. MS m/z (ESI) [M+H]+= 520.4. Attorney Docket No.: 185992002240 C.2ad: tert-butyl N-[2- [3-(hydroxymethyl)pyrrolidin-1-yl]-7-morpholino-2-quinolyl]-
Figure imgf000319_0001
2-pyridyl]oxy]ethyl]-N-methyl-carbamate
Figure imgf000319_0002
Step 1: Conditions 1 SNAr: To a solution of tert-butyl N-[2-[[5-(7-bromo-4-chloro-2- quinolyl)-2-pyridyl]oxy]ethyl]-N-methyl-carbamate (650 mg, 1.32 mmol, 1 eq) in DMSO (5 mL) was added CsF (600 mg, 3.95 mmol, 2.99 eq) and pyrrolidin-3-ylmethanol (145 mg, 1.43 mmol, 1.09 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethylacetate/Petroleum ether gradient @ 60 mL/min) to give tert-butyl N-[2-[[5-[7-bromo-4- [3-(hydroxymethyl)pyrrolidin-1-yl]-2-quinolyl]-2-pyridyl]oxy]ethyl]-N-methyl-carbamate (300 mg, 462.80 μmol, 35.09% yield, 86% purity). MS m/z (ESI) [M+H]+= 557.2. Step 2: A mixture of tert-butyl N-[2-[[5-[7-bromo-4-[3-(hydroxymethyl)pyrrolidin-1- yl]-2-quinolyl]-2-pyridyl]oxy]ethyl]-N-methyl-carbamate (280 mg, 502.26 μmol, 1 eq), morpholine (55 mg, 631.31 μmol, 55.56 μL, 1.26 eq), t-BuONa (140.00 mg, 1.46 mmol, 2.90 eq), BrettPhos Pd G3 (45 mg, 49.64 μmol, 9.88e-2 eq) in dioxane (5 mL). The reaction mixture was stirred at 80 °C for 16 hours under N2 atmosphere. After work-up the residue was purified by prep-TLC (SiO2, Dichloromethane : Methanol = 10:1) to give C.2ad (50 mg, 70.07 μmol, 13.95% yield, 79% purity). MS m/z (ESI) [M+H]+= 564.2. C.2ae: tert-butyl 4-(4-(7-methoxy-4-(cis-5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)phenyl)piperazine-1-carboxylate
Figure imgf000319_0003
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl 4- [4-(4-chloro-7-methoxy-2-quinolyl)phenyl]piperazine-1-carboxylate (740 mg, 1.63 mmol, 1 eq) , cis-5-methyloctahydro-1H-pyrrolo[3,4-c]pyridine (274.30 mg, 1.96 mmol, 1.2 eq) and Cs2CO3 (1.06 g, 3.26 mmol, 2 eq) in dioxane (8 mL) was added SPhos Pd G3 (127.19 mg, 163.01 μmol, 0.1 eq). After work-up the residue was purified by column Attorney Docket No.: 185992002240 chromatography (SiO2, Petroleum ether/Ethyl acetate=5/1 to 0/1). C.2ae (700 mg, 1.26 mmol, 77.00% yield) was obtained as a yellow solid. MS m/z (ESI) [M+H]+= 558.3. C.2af: tert-butyl (2-(4-(7-(dimethylamino)-4-(cis-5-methyloctahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000320_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-[4-chloro-7-(dimethylamino)-2-quinolyl]phenoxy]ethyl]-N-methyl-carbamate (350 mg, 767.58 μmol, 1 eq) and Cs2CO3 (600 mg, 1.84 mmol, 2.40 eq) in dioxane (5 mL) was added SPhos Pd G3 (120 mg, 153.80 μmol, 0.2 eq) and cis-5-methyloctahydro-1H- pyrrolo[3,4-c]pyridine (130 mg, 927.08 μmol, 1.21 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% DCM/MeOH gradient @ 40 mL/min) to afford C.2af (300 mg, 535.96 μmol, 69.82% yield, 100% purity) as a yellow oil. MS m/z (ESI) [M+H]+= 560.5. C.2ag: tert-butyl methyl(2-((6-(7-morpholino-4-(2-oxa-6-azaspiro[3.4]octan-6-yl)quinolin-2- yl)pyridin-3-yl)oxy)ethyl)carbamate
Figure imgf000320_0002
Step 1: Conditions 1 SNAr: To a mixture of tert-butylN-[2-[[6-(7-bromo-4-chloro-2- quinolyl)-3-pyridyl]oxy]ethyl]-N- methyl-carbamate (240 mg, 0.404 mmol, 1 eq), 2-oxa-7- azaspiro[3.4]octane oxalate (70.3 mg, 0.445 mmol, 1.1 eq) in dimethyl sulfoxide (1 mL) was added CsF (184 mg, 1.21 mmol, 3 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% dichloromethane / methanol gradient @ 25 mL/min) to give tert-butyl N-[2-[[6-[7-bromo-4- (2- oxa-7-azaspiro[3.4]octan-7-yl)-2-quinolyl]-3-pyridyl]oxy]ethyl]-N-methyl-carbamate (120 mg, 202.29 μmol, 50.04% yield, 96% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 571.2. Attorney Docket No.: 185992002240 Step 2: To a mixture of tert-butyl N-[2-[[6-[7-bromo-4-(2-oxa-7-azaspiro[3.4]octan-7- yl)-2-quinolyl] -3-pyridyl]oxy]ethyl]-N-methyl-carbamate (120 mg, 0.202 mmol, 1 eq), morpholine (35.3 mg, 0.405 mmol, 2 eq) in dioxane (2 mL) were added sodium tert-butoxide (38.9 mg, 0.405 mmol, 2 eq), Xantphos Pd G4 (19.5 mg, 0.020 mmol, 0.1 eq) at 20 °C. The mixture was stirred at 60 °C for 3 hours under nitrogen atmosphere. After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~80% Ethyl acetate/Petroleum ether gradient @ 20mL/min) to give C.2ag (90.0 mg, 0.100 mmol, 49.5% yield, 64% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 576.3. C.2ah: tert-butyl N-[2-[4-[6-fluoro-7-methoxy-4-[3-(methylcarbamoyl)pyrrolidin-1-yl]-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000321_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert-butyl N-[2- [4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (200 mg, 433.91 μmol, 1 eq), N-methylpyrrolidine-3-carboxamide (110 mg, 668.15 μmol, 1.54 eq, HCl), Cs2CO3 (425 mg, 1.30 mmol, 3.01 eq), SPhos Pd G3 (35 mg, 44.86 μmol, 1.03e-1 eq) in dioxane (4 mL). After work-up C.2ah (250 mg, 343.81 μmol, 79.23% yield, 76% purity) was obtained. MS m/z (ESI) [M+H]+= 553.3. C.2ai: tert-butyl N-[2- [7-(dimethylamino)-6-fluoro-4-(7-methyl-2,7-
Figure imgf000321_0002
diazaspiro[4.4]nonan-2-yl)-2- -N-methyl-carbamate
Figure imgf000321_0003
According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert-butyl N-[2- [[5-[4-chloro-7-(dimethylamino)-6-fluoro-2-quinolyl]-2-pyridyl]oxy]ethyl]-N-methyl- carbamate (200 mg, 421.09 μmol, 1 eq), 2-methyl-2,7-diazaspiro[4.4]nonane (89 mg, 634.69 μmol, 1.51 eq), SPhos Pd G3 (33 mg, 42.29 μmol, 0.1 eq) and Cs2CO3 (412 mg, 1.26 mmol, Attorney Docket No.: 185992002240 3 eq) in dioxane (5 mL). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient, then 0~30% MeOH/Ethyl acetate @ 18 mL/min) to give C.2ai (240 mg, 348.36 μmol, 82.73% yield, 84% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 579.4. C.2aj: tert-butyl N- [3-(difluoromethoxy)pyrrolidin-1-yl]-7-(dimethylamino)-2-
Figure imgf000322_0001
quinolyl]-2-pyridyl]oxy]ethyl]-N-methyl-carbamate
Figure imgf000322_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[[5-[4-chloro-7-(dimethylamino)-2-quinolyl]-2-pyridyl]oxy]ethyl]-N-methyl-carbamate (250 mg, 547.09 μmol, 1 eq) in dioxane (3 mL) was added 3-(difluoromethoxy)pyrrolidine (110 mg, 802.17 μmol, 1.47 eq), Cs2CO3 (600 mg, 1.84 mmol, 3.37 eq), SPhos Pd G3 (80 mg, 102.53 μmol, 1.87e-1 eq). After work-up the crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.2aj (280 mg, 482.04 μmol, 88.11% yield, 96% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 558.4. C.2ak: tert-butyl 4-(5-(7-methoxy-4-(cis-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)pyridin-2-yl)piperazine-1-carboxylate
Figure imgf000322_0003
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl 4- [5-(4-chloro-7-methoxy-2-quinolyl)-2-pyridyl]piperazine-1-carboxylate (200 mg, 439.61 μmol, 1 eq) , cis-octahydro-4H-pyrrolo[3,4-c]pyridin-4-one (140.52 mg, 659.42 μmol, 1.5 eq, 2.0 HCl) and Cs2CO3 (600 mg, 1.84 mmol, 4.19 eq) in dioxane (3 mL)was added SPhos Pd G3 (70 mg, 89.71 μmol, 2.04e-1 eq). After work-up the residue was purified by silica gel Attorney Docket No.: 185992002240 chromatography column (EA:MeOH:NH3H2O=12:1:0.5) to get C.2ak (200 mg, 247.02 μmol, 56.19% yield, 69% purity) as a yellow oil. MS m/z (ESI) [M+H]+= 559.3. C.2al: tert-butyl (2-(4-(6-fluoro-7-methoxy-4-(4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000323_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (200 mg, 433.91 μmol, 1 eq) in dioxane (3 mL) was added  cis-octahydro-4H-pyrrolo[3,4- c]pyridin-4-one (140 mg, 656.96 μmol, 1.52 eq, HCl), SPhos Pd G3 (338.56 mg, 433.91 μmol, 1 eq), Cs2CO3 (526 mg, 1.61 mmol, 3.00 eq). After work-up the crude product was purified by prep-TLC (SiO2, PE: EA = 1:1, Rf=0.1) to give C.2al (190 mg, 97.58 μmol, 22.49% yield, 29% purity) as a white solid. MS m/z (ESI) [M+H]+= 565.2. C.2am: tert-butyl N-[2-[4-[6-fluoro-7-methoxy-4-(6-oxo-2,7-diazaspiro[4.5]decan-2-yl)-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000323_0002
Step 1: To a solution of tert-butyl 6-oxo-2,7-diazaspiro[4.5]decane-2-carboxylate (300 mg, 1.18 mmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M, 2 mL) at 25°C .The mixture was stirred at 25 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 2,7-diazaspiro[4.5]decan-6-one (220 mg, crude, HCl). 1H NMR (400 MHz, CD3OD) d (ppm): 3.64 (d, J = 11.7 Hz, 1H), 3.55 - 3.40 (m, 2H), 3.37 - 3.32 (m, 2H), 3.02 (d, J = 11.7 Hz, 1H), 2.43 (ddd, J = 5.1, 8.0, 13.3 Hz, 1H), 2.05 - 1.85 (m, 5H). Step 2: According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert- butyl N-[2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (250 mg, 542.39 μmol, 1 eq), 2,7-diazaspiro[4.5]decan-6-one (100 mg, 648.47 μmol, 1.2 eq), Attorney Docket No.: 185992002240 Cs2CO3 (530 mg, 1.63 mmol, 3 eq), SPhos Pd G3 (45 mg, 57.67 μmol, 1.06e-1 eq) in dioxane (5 mL). After work-up the residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 0:1) to give C.2am (125 mg, 166.11 μmol, 30.63% yield, 76.9% purity). MS m/z (ESI) [M+H]+= 579.3. C.2an: tert-butyl (2-(4-(6-fluoro-7-methoxy-4-(4-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)quinolin-2-yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000324_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]oxy]ethyl]-N-methyl-carbamate (250 mg, 541.23 μmol, 1 eq) in dioxane (5 mL) was added hexahydropyrrolo[3,4-c]pyrrol- 1(2H)-one (150 mg, 662.92 μmol, 1.22 eq) , SPhos Pd G3 (70 mg, 89.71 μmol, 1.66e-1 eq) , Cs2CO3 (600 mg, 1.84 mmol, 3.40 eq). After work-up the crude product was purified by prep-TLC (SiO2, PE: EA = 1:1, Rf=0.1) to give C.2an (350 mg, 158.91 μmol, 29.36% yield, 25% purity) as a white solid. MS m/z (ESI) [M+H]+= 551.3. C.2ao: tert-butyl N-[2-[4-[4- dioxo-2thia-7-azaspiro[3.4]octan-7-yl)-6-fluoro-7-methoxy-
Figure imgf000324_0002
2-quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000324_0003
According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert-butyl N-[2- [4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (200 mg, 433.91 μmol, 1 eq) , 2thia-7-azaspiro[3.4]octane 2,2-dioxide (100 mg, 505.86 μmol, 1.17 eq, HCl) , Cs2CO3 (425 mg, 1.30 mmol, 3.01 eq) , SPhos Pd G3 (35 mg, 44.86 μmol, 1.03e-1 eq) in dioxane (5 mL) . After work-up the residue was triturated with Ethyl acetate (10 ml) at 25°C for 30 min to give C.2ao (160 mg, 256.79 μmol, 59.18% yield, 94% purity). MS m/z (ESI) [M+H]+= 586.2. Attorney Docket No.: 185992002240 C.2ap: tert-butylN-[2- [6-fluoro-7-methoxy-4-(3-methoxypyrrolidin-1-yl)-2-quinolyl] -2-
Figure imgf000325_0001
pyridyl] -methyl-amino]ethyl]-N-methyl-carbamate
Figure imgf000325_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a mixture of tert-butyl N- [2-[[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]- methyl-amino]ethyl]-N-methyl- carbamate (350 mg, 0.538 mmol, 1 eq), 3-methoxypyrrolidine (111 mg, 0.807 mmol, 1.5 eq, HCl) in dioxane (3.0 mL) were added Xanphos Pd G4 (42.0 mg, 0.0538 μmol, 0.1 eq), Cs2CO3 (526 mg, 1.61 mmol, 3 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give C.2ap (270 mg, 0.470 mmol, 87.4% yield, 94% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 540.4. C.2aq: tert-butyl (2-((5-(6-fluoro-7-methoxy-4-(cis-4-oxooctahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate
Figure imgf000325_0003
According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert-butyl N-[2- [[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]oxy]ethyl]-N-methyl-carbamate (200 mg, 432.98 μmol, 1 eq) , cis-octahydro-4H-pyrrolo[3,4-c]pyridin-4-one (140 mg, 656.96 μmol, 1.52 eq, HCl), Cs2CO3 (425 mg, 1.30 mmol, 3.01 eq), SPhos Pd G3 (35 mg, 44.86 μmol, 1.04e-1 eq) in dioxane (3 mL). After work-up the residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 0:1) to give C.2aq (70 mg, 95.79 μmol, 22.12% yield, 77.4% purity). MS m/z (ESI) [M+H]+= 566.2. Attorney Docket No.: 185992002240 C.2ar: tert-butyl (2-(4-(6-fluoro-7-methoxy-4-(cis-5-methyl-4-oxooctahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000326_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (250 mg, 542.39 μmol, 1 eq) in dioxane (3 mL) was added cis-5-methyloctahydro-4H-pyrrolo[3,4- c]pyridin-4-one (120 mg, 778.16 μmol, 1.43 eq), SPhos Pd G3 (70 mg, 89.71 μmol, 1.65e-1 eq), Cs2CO3 (600 mg, 1.84 mmol, 3.4 eq). After work-up the crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash? Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.2ar (270 mg, 443.26 μmol, 81.72% yield, 95% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 579.3. C.2as: tert-butyl (2-(4-(7-methoxy-4-cis-5-methyl-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin- 2-yl)quinolin-2-yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000326_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert-butyl N-[2- [4-(4-chloro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (200 mg, 451.53 μmol, 1 eq), cis-5-methyloctahydro-4H-pyrrolo[3,4-c]pyridin-4-one (104.45 mg, 677.30 μmol, 1.5 eq), SPhos Pd G3 (35.23 mg, 45.15 μmol, 0.1 eq), Cs2CO3 (441.36 mg, 1.35 mmol, 3 eq) in dioxane (2 mL). After work-up the residue was purified by prep-TLC (SiO2, PE:EtOAc = 0:1) to give C.2as (200 mg, 353.14 μmol, 78.21% yield, 99% purity) as yellow oil. MS m/z (ESI) [M+H]+= 561.3. Attorney Docket No.: 185992002240 C.2at: tert-butyl N-[2-[4-[4-[3-(dimethylcarbamoyl)pyrrolidin-1-yl]-6-fluoro-7-methoxy-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000327_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert-butyl N-[2- [4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (250 mg, 542.39 μmol, 1 eq), N,N-dimethylpyrrolidine-3-carboxamide (145 mg, 811.60 μmol, 1.5 eq, HCl), Cs2CO3 (530 mg, 1.63 mmol, 3 eq), SPhos Pd G3 (45 mg, 57.67 μmol, 1.06e-1 eq) in dioxane (3 mL). After work-up C.2at (280 mg, 380.47 μmol, 70.15% yield, 77% purity) was obtained. MS m/z (ESI) [M+H]+= 567.4. C.2au: tert-butyl (2-((5-(7-(dimethylamino)-4-(cis-5-methyl-4-oxooctahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate
Figure imgf000327_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[[5-[4-chloro-7-(dimethylamino)-2-quinolyl]-2-pyridyl]oxy]ethyl]-N-methyl-carbamate (250 mg, 547.09 μmol, 1 eq) in dioxane (2 mL) was added cis-5-methyloctahydro-4H- pyrrolo[3,4-c]pyridin-4-one (120 mg, 778.16 μmol, 1.42 eq), SPhos Pd G3 (80 mg, 102.53 μmol, 1.87e-1 eq), Cs2CO3 (600 mg, 1.84 mmol, 3.37 eq). After work-up the crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/PE gradient @ 40 mL/min) to give C.2au (270 mg, 401.68 μmol, 73.42% yield, 85.5% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 575.2. Attorney Docket No.: 185992002240 C.2av: tert-butyl N-[2-[4-[4-(2,2-dioxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-c]pyrrol-5-yl)-6- fluoro-7-methoxy-2-quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000328_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert-butyl N-[2- [4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (150 mg, 325.43 μmol, 1 eq), 3,3a,4,5,6,6a-hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide (78.70 mg, 488.15 μmol, 1.5 eq), Cs2CO3 (318.10 mg, 976.30 μmol, 3 eq), SPhos Pd G3 (25.39 mg, 32.54 μmol, 0.1 eq) in dioxane (2 mL). After work-up the residue was purified by prep-TLC (SiO2, PE:Ethyl acetate = 0:1) to give C.2av (180 mg, 255.09 μmol, 78.38% yield, 83% purity) as a white solid. MS m/z (ESI) [M+H]+= 586.4. C.2aw: tert-butyl 3-(4-(6-fluoro-7-methoxy-4-(4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)phenoxy)azetidine-1-carboxylate
Figure imgf000328_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl 3- [4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl) phenoxy]azetidine-1-carboxylate (230 mg, 501 μmol, 1 eq), cis -octahydropyrrolo[3, 4-c]pyridin-4-one (70.3 mg, 501 μmol, 1 eq) and Cs2CO3 (163.3 mg, 501.2 μmol, 1 eq) in dioxane (2.50 mL) was added SPhos Pd G3 (39.1 mg, 50.1 μmol, 0.1 eq). After work-up the residue was purified by prep-TLC (SiO2, PE:EtOAc = 1:1) to give compound C.2aw (140 mg, 248.8 μmol, 49.7% yield) as yellow oil. MS m/z (ESI) [M+H]+= 563.3. Attorney Docket No.: 185992002240 C.2ax: tert-butyl 3-(4-(6-fluoro-7-methoxy-4-(4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)phenoxy)pyrrolidine-1-carboxylate
Figure imgf000329_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl 3- [4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl) phenoxy]pyrrolidine-1-carboxylate (260 mg, 550 μmol, 1 eq), cis-octahydropyrrolo[3, 4-c]pyridin-4-one (77.07 mg, 550 μmol, 1 eq) and Cs2CO3 (358 mg, 1.1 mmol, 2 eq) in dioxane (3 mL) was added SPhos Pd G3 (42.9 mg, 54.9 μmol, 0.1 eq). After work-up the residue was purified by prep-TLC (SiO2, PE:EtOAc = 1:1) to give C.2ax (200 mg, 347 μmol, 63.1% yield) as yellow oil. MS m/z (ESI) [M+H]+= 577.3. C.2ay: tert-butyl (2-(4-(4-(cis-7,7-difluoro-5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)-6-fluoro-7-methoxyquinolin-2-yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000329_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert-butyl N-[2- [4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (150 mg, 325.43 μmol, 1 eq), cis-7,7-difluoro-5-methyloctahydro-1H-pyrrolo[3,4-c]pyridine (114.69 mg, 650.87 μmol, 2 eq), SPhos Pd G3 (25.39 mg, 32.54 μmol, 0.1 eq), Cs2CO3 (318.10 mg, 976.30 μmol, 3 eq) in dioxane (2 mL). After work-up the residue was purified by prep-TLC (SiO2, DCM: MeOH = 10:1) to give C.2ay (52 mg, 82.24 μmol, 25.27% yield, 95% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 601.3. Attorney Docket No.: 185992002240 C.2az: tert-butyl 3-(((5-(6-fluoro-7-methoxy-4-(cis-5-methyloctahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)pyridin-2-yl)oxy)methyl)azetidine-1-carboxylate
Figure imgf000330_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl 3- [[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate (0.3 g, 633.01 μmol, 1 eq) , cis-5-methyloctahydro-1H-pyrrolo[3,4-c]pyridine (100 mg, 713.14 μmol, 1.13 eq) in dioxane (6 mL) was added SPhos Pd G3 (49.39 mg, 63.30 μmol, 0.1 eq) and Cs2CO3 (618.74 mg, 1.90 mmol, 3 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% Dichloromethane : Methanol gradient @ 60mL/min) to C.2az (150 mg, 233.69 μmol, 36.92% yield, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 578.4. C.2aaa: tert-butyl N-[2-[4-[6-fluoro-7-methoxy-4-(2-methyl-2, 6-diazaspiro[3.4]octan-6-yl) - 2-quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000330_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl) phenoxy]ethyl]-N-methyl-carbamate (250 mg, 542.39 μmol, 1 eq) and 2-methyl-2, 7-diazaspiro[3.4]octane (100.00 mg, 792.40 μmol, 1.46 eq) in dioxane (5 mL) was added SPhos Pd G3 (60 mg, 76.90 μmol, 1.42e-1 eq) and Cs2CO3 (500.00 mg, 1.53 mmol, 2.83 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% MeOH/ Ethyl acetate (1% NH3•H2O) gradient @ 50 mL/min) to give C.2aaa (250 mg, 454.00 μmol, 83.70% yield, 100% purity) as yellow gum. MS m/z (ESI) [M+H]+= 551.4. Attorney Docket No.: 185992002240 C.2aab: tert-butyl (2-((4-(6-fluoro-7-methoxy-4-(5-methyloctahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)phenyl)thio)ethyl)(methyl)carbamate
Figure imgf000331_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert-butyl N-[2- [4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenyl]sulfanylethyl]-N-methyl-carbamate (250 mg, 524.12 μmol, 1 eq), cis-5-methyloctahydro-1H-pyrrolo[3,4-c]pyridine (110 mg, 784.45 μmol, 1.5 eq), SPhos Pd G3 (41 mg, 52.55 μmol, 0.1 eq) and Cs2CO3 (512 mg, 1.57 mmol, 3 eq) in dioxane (5 mL). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 18 mL/min) to give C.2aab (180 mg, 213.86 μmol, 40.80% yield, 69% purity) as yellow oil. MS m/z (ESI) [M+H]+= 581.3. C.2aac: 6-fluoro-7-methoxy-4-(cis-5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-2-(4- ((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)oxy)phenyl)quinoline
Figure imgf000331_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of 2-[[4-[4-(4- chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]imidazol-1-yl]methoxy]ethyl-trimethyl- silane (350 mg, 699.95 μmol, 1 eq) in dioxane (3 mL) was added cis-5-methyloctahydro-1H- pyrrolo[3,4-c]pyridine (210.00 mg, 1.19 mmol, 1.70 eq, HCl), Cs2CO3 (700.00 mg, 2.15 mmol, 3.07 eq), SPhos Pd G3 (61.25 mg, 78.50 μmol, 1.12e-1 eq). After work-up the crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.2aac (290 mg, 416.89 μmol, 59.56% yield, 86.8% purity) as a yellow solid. Attorney Docket No.: 185992002240 C.2aad: tert-butyl 4-(5-(6-fluoro-7-methoxy-4-(cis-4-oxooctahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)pyridin-2-yl)piperazine-1-carboxylate
Figure imgf000332_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl 4- [5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]piperazine-1-carboxylate (300 mg, 634.33 μmol, 1 eq), octahydro-4H-pyrrolo[3,4-c]pyridin-4-one (109 mg, 707.45 μmol, 1.12 eq) in dioxane (5 mL) were added SPhos Pd G3 (50 mg, 64.08 μmol, 1.01e-1 eq) and Cs2CO3 (420 mg, 1.29 mmol, 2.03 eq). After work-up the residue was purified by prep-TLC (Plate 1: Petroleum ether : Ethyl acetate=0:1 ) to give C.2aad (160 mg, 141.85 μmol, 22.36% yield, 60% purity) as a yellow solid. C.2aae: tert-butyl N-[2-[4-[7-(dimethylamino)-6-fluoro-4-(3-methoxypyrrolidin-1-yl)-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000332_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-[4-chloro-7-(dimethylamino)-6-fluoro-2-quinolyl]phenoxy]ethyl]-N-methyl-carbamate (200 mg, 421.97 μmol, 1 eq), 3-methoxypyrrolidine (87.10 mg, 632.96 μmol, 1.5 eq, HCl) in dioxane (4 mL) was added SPhos Pd G3 (32.92 mg, 42.20 μmol, 0.1 eq) and Cs2CO3 (412.46 mg, 1.27 mmol, 3 eq) at 25°C. After work-up C.2aae (0.2 g, 371.30 μmol, 87.99% yield) was obtained as a yellow solid. MS m/z (ESI) [M+H]+= 539.2. Attorney Docket No.: 185992002240 C.2aaf: tert-butyl N-[2-[4-[6-fluoro-7-methoxy-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000333_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert-butyl N-[2- [4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate oxalate (200 mg, 433.91 μmol, 1 eq) , 2-oxa-7-azaspiro[3.4]octane (90.00 mg, 568.99 μmol, 1.31 eq), Cs2CO3 (425.00 mg, 1.30 mmol, 3.01 eq), SPhos Pd G3 (40.00 mg, 51.27 μmol, 1.18e-1 eq) in dioxane (3 mL). After work-up C.2aaf (200 mg, 279.01 μmol, 64.30% yield, 75% purity) was obtained. MS m/z (ESI) [M+H]+= 538.4. C.2aag: tert-butyl N-[2- [6-fluoro-4-[3-(hydroxymethyl)pyrrolidin-1-yl]-7-
Figure imgf000333_0002
(trideuteriomethoxy)-2-quinolyl]-3-pyridyl]oxy]ethyl]-N-methyl-carbamate
Figure imgf000333_0003
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[[6-[4-chloro-6-fluoro-7-(trideuteriomethoxy)-2-quinolyl]-3-pyridyl]oxy]ethyl]-N-methyl- carbamate (180 mg, 387.15 μmol, 1 eq) in dioxane (3 mL) was added pyrrolidin-3- ylmethanol (90.00 mg, 889.80 μmol, 2.30 eq), SPhos Pd G3 (90.00 mg, 115.35 μmol, 2.98e-1 eq), Cs2CO3 (450.00 mg, 1.38 mmol, 3.57 eq). After work-up the crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.2aag (190 mg, 335.07 μmol, 86.55% yield, 93.4% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 530.2. Attorney Docket No.: 185992002240 C.2aah: tert-butyl cis-tert-butyl (2-(4-(6-fluoro-7-(methoxy-d3)-4-(5-methyloctahydro-2H- pyrrolo[3,4-c]pyridin-2-yl)quinolin-2-yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000334_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-[4-chloro-6-fluoro-7-(trideuteromethoxy) -2-quinolyl]phenoxy]ethyl]-N-methyl- carbamate (200 mg, 431.09 μmol, 1 eq) in dioxane (5 mL) was added SPhos Pd G3 (40 mg, 51.27 μmol, 1.19e-1 eq) and cis-5-methyloctahydro-1H-pyrrolo[3,4-c]pyridine (400 mg, 2.26 mmol, 5.25 eq, HCl), Cs2CO3 (700 mg, 2.15 mmol, 4.98 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% Dichloromethane /Methanol gradient @ 40 mL/min) to afford C.2aah (100 mg, 176.15 μmol, 40.86% yield, 100% purity) as yellow oil. MS (ESI) [M+H]+= 568.4. C.2aai: tert-butylN-[2-[4-[6-fluoro-7-methoxy-4-(2-oxo-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- b]pyrrol -5-yl)-2-quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000334_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a mixture of tert-butylN- [2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]- N-methyl-carbamate (200 mg, 433.91 μmol, 1 eq), 3,3a,4,5,6,6a-hexahydro-1H-pyrrolo[3,4-b] pyrrol-2-one (65 mg, 515.24 μmol, 1.19 eq) in dioxane (3 mL) were added SPhos Pd G3 (35 mg, 44.86 μmol, 1.03e-1 eq), Cs2CO3 (300 mg, 920.76 μmol, 2.12 eq). After work-up the residue was purified by prep-TLC (SiO2: petroleum ether: ethyl acetate = 1:1) to give C.2aai (150 mg, 266.97 μmol, 61.53% yield, 98% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 551.3. Attorney Docket No.: 185992002240 C.2aaj, C.2aak: tert-butyl (2-(4-(7-methoxy-4-((3aR,7aS)-4-oxooctahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)phenoxy)ethyl)(methyl)carbamate& tert-butyl (2-(4-(7-methoxy- 4-((3aS,7aR)-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000335_0001
According to Scheme 3 Step 2: Conditions 1 SNAr: To a solution of tert-butyl N-[2- [4-(4-chloro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (1 g, 2.26 mmol, 1 eq) in DMSO (20 mL) was added cis-octahydro-4H-pyrrolo[3,4-c]pyridin-4-one hydrochloride (1 g, 4.69 mmol, 2.08 eq, 2 HCl) and CsF (1.00 g, 6.58 mmol, 2.92 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~20% EtOAc/Petroleum ether gradient @ 100 mL/min) to afford a residue. The residue was purified by prep-SFC (column: REGIS(S,S)WHELK-O1(250mm*25mm,10um);mobile phase: [CO2-ACN/i-PrOH (0.1% NH3H2O)]; B%:70%, isocratic elution mode). After Prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to C.2aaj (200 mg, 365.86 μmol, 16.21% yield, 100% purity) as a colorless oil MS m/z (ESI) [M+H]+= 547.3 and C.2aak (200 mg, 362.20 μmol, 16.04% yield, 99% purity) as a colorless oil MS m/z (ESI) [M+H]+= 547.3. C.2aal: tert-butyl 3-(4-(6-fluoro-7-methoxy-4-(5-methyl-4-oxooctahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)phenoxy)azetidine-1-carboxylate
Figure imgf000335_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert-butyl 3-[4- (4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]azetidine-1-carboxylate (140 mg, 305.07 μmol, 1 eq), cis-5-methyloctahydro-4H-pyrrolo[3,4-c]pyridin-4-one (94.09 mg, 610.14 μmol, 2 eq), SPhos Pd G3 (23.80 mg, 30.51 μmol, 0.1 eq), Cs2CO3 (298.19 mg, 915.21 μmol, 3 eq) Attorney Docket No.: 185992002240 in dioxane (2 mL). After work-up the residue was purified by prep-TLC (SiO2, Ethyl acetate : Methanol = 10:1) to give C.2aal (120 mg, 181.04 μmol, 59.34% yield, 87% purity) as yellow oil. MS m/z (ESI) [M+H]+= 577.3. C.2aam: tert-butyl N-[2-[4-[6-fluoro-7-methoxy-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)- 2-quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000336_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: A mixture of tert-butyl N-[2- [4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (150 mg, 325.43 μmol, 1 eq), 2-methyl-2,7-diazaspiro[4.4]nonane (69 mg, 492.06 μmol, 1.51 eq), SPhos Pd G3 (25 mg, 32.04 μmol, 9.85e-2 eq) and Cs2CO3 (318 mg, 976.00 μmol, 3 eq) in dioxane (5 mL). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 18 mL/min) to give C.2aam (150 mg, 254.21 μmol, 78.11% yield, 95.7% purity) as yellow oil. MS m/z (ESI) [M+H]+= 565.3. C.2aan: tert-butyl N-[2-[4-[6-fluoro-7-methoxy-4-(6-methyl-5-oxo-2,6- diazaspiro[3.5]nonan-2-yl)-2- carbamate
Figure imgf000336_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (300 mg, 650.87 μmol, 1 eq) in dioxane (3 mL) was added 6-methyl-2,6-diazaspiro[3.5]nonan-5- one (120 mg, 778.16 μmol, 1.20 eq) , SPhos Pd G3 (80 mg, 102.53 μmol, 1.58e-1 eq) , Cs2CO3 (650 mg, 1.99 mmol, 3.07 eq). After work-up the crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.2aan (350 mg, 575.80 μmol, 88.47% yield, 95.2% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 579.3. Attorney Docket No.: 185992002240 C.2aao: tert-butyl N-[2-[4-[4-[3-[(dimethylamino) methyl]pyrrolidin-1-yl]-6-fluoro-7- methoxy-2-quinolyl]phenoxy] ethyl]-N-methyl-carbamate
Figure imgf000337_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl) phenoxy]ethyl]-N-methyl-carbamate (170.00 mg, 368.82 μmol, 1 eq) and N, N-dimethyl-1-pyrrolidin-3-yl-methanamine (100 mg, 779.94 μmol, 2.11 eq) in dioxane (5 mL) was added SPhos Pd G3 (50 mg, 64.08 μmol, 1.74e-1 eq) and Cs2CO3 (400 mg, 1.23 mmol, 3.33 eq). After work-up the crude material was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% MeOH/ Ethyl acetate (1% NH3•H2O) gradient @ 50 mL/min) to give C.2aao (160 mg, 277.92 μmol, 75.35% yield, 96% purity) as yellow solid. MS m/z (ESI) [M+H]+= 553.4. C.2aap: tert-butyl 3-((4-(6-fluoro-7-methoxy-4-(5-methyl-4-oxooctahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)phenoxy)methyl)azetidine-1-carboxylate
Figure imgf000337_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl 3- [[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]methyl]azetidine-1-carboxylate (200 mg, 422.89 μmol, 1 eq), cis-5-methyloctahydro-4H-pyrrolo[3,4-c]pyridin-4-one (80 mg, 518.78 μmol, 1.23 eq) and Cs2CO3 (400 mg, 1.23 mmol, 2.90 eq) in dioxane (3 mL) was added SPhos Pd G3 (30 mg, 38.45 μmol, 9.09e-2 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% DCM/MeOH gradient @ 40 mL/min) to C.2aap (140 mg, 231.80 μmol, 54.81% yield, 97.8% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 591.3. Attorney Docket No.: 185992002240 C.2aaq: tert-butyl N-[2-[4-[7-methoxy-4-[(3S) -3-(methylcarbamoyl) pyrrolidin-1-yl]-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000338_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-7-methoxy-2-quinolyl) phenoxy]ethyl]-N-methyl-carbamate (150 mg, 338.65 μmol, 1 eq) (EW30832-1647-P1) and (3S) -N-methylpyrrolidine-3-carboxamide (100 mg, 607.41 μmol, 1.79 eq, HCl) in dioxane (5 mL) was added SPhos Pd G3 (40 mg, 51.26 μmol, 1.51e-1 eq) and Cs2CO3 (400 mg, 1.23 mmol, 3.63 eq). After work-up the crude material was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% MeOH/ Ethyl acetate gradient @ 50 mL/min) to give C.2aaq (120 mg, 220.09 μmol, 64.99% yield, 98.06% purity) as yellow solid. MS m/z (ESI) [M+H]+= 535.4. C.2aar & C.2aas: tert-butyl N-[2-[4-[7-methoxy-4-(3-methyl-2,2-dioxo-2thia-3,7- diazaspiro[4.4]nonan-7-yl)-2-quinolyl]phenoxy]ethyl]-N-methyl-carbamate & tert-butyl N- [2-[4- dimethyl-2,2-dioxo-2thia-3,7-diazaspiro[4.4]nonan-7-yl)-7-methoxy-2-
Figure imgf000338_0002
quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000338_0003
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-7-methoxy-2-quinolyl) phenoxy]ethyl]-N-methyl-carbamate (200 mg, 451.53 μmol, 1 eq), 1, 3-dimethyl-2thia-3,7-diazaspiro[4.4]nonane 2, 2-dioxide/3-methyl-2thia-3,7- diazaspiro[4.4]nonane 2, 2-dioxide (124.71 mg, 316.07 μmol, 0.7 eq) and Cs2CO3 (588.47 mg, 1.81 mmol, 4 eq) in dioxane (4.00 mL) was added SPhos Pd G3 (35.23 mg, 45.15 μmol, 0.1 eq). After work-up the residue was purified by prep-TLC (SiO2, PE: EtOAc = 1:1). C.2aar & C.2aas (150 mg, 124.22 μmol, 27.51% yield) were obtained as yellow oil. MS m/z (ESI) [M+H]+= 597.3 & MS m/z (ESI) [M+H]+= 611.3. Attorney Docket No.: 185992002240 C.2aat: tert-butylN-[2-[4-[6-fluoro-7-methoxy-4-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000339_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (200 mg, 433.91 μmol, 1 eq) in dioxane (2 mL) was added 2,7-diazaspiro[4.4]nonan-3-one (80 mg, 570.68 μmol, 1.32 eq), SPhos Pd G3 (70 mg, 89.71 μmol, 2.07e-1 eq), Cs2CO3 (500 mg, 1.53 mmol, 3.54 eq). After work-up the crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.2aat (130 mg, 206.98 μmol, 47.70% yield, 89.9% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 565.4. C.2aau: tert-butyl (2-(4-(7-ethoxy-4-(4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000339_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-7-ethoxy-2-quinolyl) phenoxy]ethyl]-N-methyl-carbamate (180 mg, 393.91 μmol, 1 eq) in dioxane (2 mL) was added cis-ydro-4H-pyrrolo[3,4-c]pyridin-4-one (65 mg, 463.68 μmol, 1.18 eq), SPhos Pd G3 (30 mg, 38.45 μmol, 9.76e-2 eq) and Cs2CO3 (390 mg, 1.20 mmol, 3.04 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Methanol gradient @ 40 mL/min) to afford C.2aau (100 mg, 178.35 μmol, 45.28% yield, 100% purity) as yellow oil. MS m/z (ESI) [M+H]+= 561.3. Attorney Docket No.: 185992002240 C.2aav: tert-butyl N-[2-[4-[7-methoxy-4-[3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000340_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (250 mg, 564.42 μmol, 1 eq) in dioxane (3 mL) was added 1-(pyrrolidin-3-ylmethyl)pyrrolidine (100 mg, 648.29 μmol, 1.15 eq), SPhos Pd G3 (50 mg, 64.08 μmol, 1.14e-1 eq), Cs2CO3 (600 mg, 1.84 mmol, 3.26 eq. After work-up the crude product was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give C.2aav (150 mg, 267.51 μmol, 47.40% yield, 100% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 561.4. C.2aaw: tert-butyl (2-(4-(8-fluoro-7-methoxy-4-(4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin- 2-yl)quinolin-2-yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000340_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-8-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (80 mg, 173.56 μmol, 1 eq) in dioxane (2 mL) was added cis-octahydro-4H-pyrrolo[3,4-c]pyridin-4- one (40 mg, 285.34 μmol, 1.64 eq), SPhos Pd G3 (50 mg, 64.08 μmol, 3.69e-1 eq), Cs2CO3 (200 mg, 613.84 μmol, 3.54 eq). After work-up the crude product was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 0~10% DCM/MeOH ether gradient @ 40 mL/min) to give C.2aaw (80 mg, 138.14 μmol, 79.59% yield, 97.5% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 565.2. Attorney Docket No.: 185992002240 C.2aax: tert-butyl N-[2-[4-[6-fluoro-7-methoxy-4-[(3S) -3-(methylcarbamoyl) pyrrolidin-1- yl]-2-quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000341_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl) phenoxy]ethyl]-N-methyl-carbamate (200 mg, 433.91 μmol, 1 eq) and (3S) -N-methylpyrrolidine-3-carboxamide (120 mg, 728.90 μmol, 1.68 eq, HCl) in dioxane (5 mL) was added SPhos Pd G3 (50.00 mg, 64.08 μmol, 1.48e-1 eq) and Cs2CO3 (400 mg, 1.23 mmol, 2.83 eq). After work-up the crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% MeOH/ Ethyl acetate gradient @ 50 mL/min) to give C.2aax (220 mg, 346.34 μmol, 79.82% yield, 87% purity) as yellow solid. MS m/z (ESI) [M+H]+= 553.3. C.2aay: cis-tert-butyl (2-(4-(7-(methoxy-d3)-4-(4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000341_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-[4-chloro-7-(trideuteriomethoxy) -2-quinolyl]phenoxy]ethyl]-N-methyl-carbamate (200 mg, 448.48 μmol, 1 eq) in dioxane (3 mL) was added cis-octahydro-4H-pyrrolo[3,4- c]pyridin-4-one (80 mg, 570.68 μmol, 1.27 eq), SPhos Pd G3 (40 mg, 51.27 μmol, 1.14e-1 eq) and Cs2CO3 (440 mg, 1.35 mmol, 3.01 eq). After work-up the crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate /Methano gradient @ 40 mL/min) to afford C.2aay (210 mg, 382.04 μmol, 85.19% yield, 100% purity) as yellow oil. MS m/z (ESI) [M+H]+= 550.5. Attorney Docket No.: 185992002240 C.2aaz: cis-tert-butyl (2-(4-(7-methoxy-4-(2-oxohexahydropyrrolo[3,4-b]pyrrol-5(1H)- yl)quinolin-2-yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000342_0001
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a mixture of tert-butyl N- [2-[4-(4-chloro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl- carbamate (500 mg, 1.13 mmol, 1 eq), cis-hexahydropyrrolo[3,4-b]pyrrol-2(1H)-one (200 mg, 1.59 mmol, 1.4 eq) in dioxane (8 mL) were added SPhos Pd G3 (90.0 mg, 0.115 mmol, 1.02e-1 eq) and Cs2CO3 (1.10 g, 3.39 mmol, 3.00 eq) at 25°C. After work-up the crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% EtOAc/PE gradient @ 40 mL/min) to give C.2aaz (120 mg, 0.153 mmol, 13.6% yield, 68% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 553.3. C.2aba: tert-butyl N-[2-[4-[7-methoxy-4-(3-methyl-2-oxo-1,7-diazaspiro[4.4]nonan-7-yl)-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000342_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To mixture of tert-butyl N- [2-[4-(4-chloro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (130 mg, 293.50 μmol, 1 eq) , 3-methyl-1,7-diazaspiro[4.4]nonan-2-one (84.50 mg, 443.17 μmol, 1.51 eq, HCl) were added SPhos Pd G3 (26.00 mg, 33.32 μmol, 1.14e-1 eq) , Cs2CO3 (383.50 mg, 1.18 mmol, 4.01 eq) in dioxane (2 mL). After work-up the crude product was purified by prep-TLC (SiO2, PE/EtOAc 10/1) to give C.aba (80 mg, 119.85 μmol, 40.84% yield, 84% purity) as yellow oil. MS m/z (ESI) [M+H]+= 561.4. Attorney Docket No.: 185992002240 C.2abb: cis-tert-butyl N-[2-[4-[4-(2,2-dioxo-2thia-7-azaspiro[3.4]octan-7-yl)-6-fluoro-7- pent-4-ynoxy-2-quinolyl]phenoxy]ethyl]-N-methyl-carbamate
Figure imgf000343_0001
According to Scheme 3 Step 2: Conditions 1 SNAr: To a solution of tert-butyl N-[2- [4-(4-chloro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (250 mg, 564.42 μmol, 1 eq) in DMSO (2 mL) was added hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one (120.00 mg, 951.20 μmol, 1.69 eq), CsF (300 mg, 1.97 mmol, 3.50 eq), then the resulting mixture was purged with N2 for three times and stirred at 100°C for 12 hours. The reaction mixture was partitioned between EtOAc (100 mL) and water (80 mL), washed with brine(70 mL), died over Na2SO4, filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~30% EtOAc/PE gradient @ 40 mL/min) to give C.2abb (160 mg, 277.57 μmol, 49.18% yield, 92.4% purity) as a yellow solid. C.2abc: tert-butyl (2-(4-(6-fluoro-7-methoxy-4-((3aS,6aS)-2-oxohexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)quinolin-2-yl)phenoxy)ethyl)(methyl)carbamate
Figure imgf000343_0002
According to Scheme 3 Step 2: Conditions 3 Buchwald: To a mixture of tert-butyl N- [2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (150 mg, 325 μmol, 1.00 eq), (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-2(1H)-one (crude 50.0 mg, 396 μmol, 1.22 eq) in dioxane (3.00 mL) were added SPhos Pd G3 (32.0 mg, 41.01 μmol, 1.26e-1 eq) and Cs2CO3 (370 mg, 1.14 mmol, 3.49 eq) at 25°C. After work-up the crude product was purified by prep-TLC (SiO2: EtOAc/MeOH 10/1) to give C.2abc (60.0 mg, 105 μmol, 32.1% yield, 97.0% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 551.2. Attorney Docket No.: 185992002240 D.1a: tert-butyl (cis)-2-[2-[6-(dimethylamino)-3-pyridyl]-7-methoxy-4-quinolyl]- 3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c] pyridine-5-carboxylate
Figure imgf000344_0001
According to Scheme 5 Step 1: Conditions 4 Buchwald: 5-(4-chloro-7-methoxy-2- quinolyl)-N, N-dimethyl-pyridin-2-amine A.5a (0.20 g, 0.64 mmol, 1.0 eq) in dioxane (4 mL). After work-up the residue obtained was purified by prep-TLC (SiO2, PE/EtOAc = 0:1) to give D.1a (0.30 g, 0.59 mmol, 92% yield, 98% purity), which was obtained as black, brown oil. MS m/z (ESI) [M+H]+= 504.3. D.1b: tert-butyl 2-[2-[6-(azetidin-1-yl)-3-pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-2,7-
Figure imgf000344_0002
According to Scheme 5 Step 1: Conditions 1 Buchwald: 2-[6-(azetidin-1-yl) -3- pyridyl]-4-chloro-6-fluoro-7-methoxy-quinoline A.5b (0.20 g, 0.58 mmol, 1.0 eq). After work-up D.1b (0.30 g, crude) was obtained as a yellow solid. MS m/z (ESI) [M+H]+= 548.3. D.1c: tert-butyl 2-[2-(4-acetamidophenyl)-6-fluoro-7-methoxy-4-quinolyl]-2,7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000344_0003
According to Scheme 5 Step 1: Conditions 1 Buchwald: To a mixture of A.5i (0.11 g, 0.32 mmol, 1.0 eq) in dioxane (3.0 mL) was added tert-butyl 2, 7-diazaspiro[4.5]decane-7- carboxylate (90 mg, 0.37 mmol, 1.2 eq), BrettPhos Pd G3 (30 mg, 33 μmol, 0.10 eq) and t- BuONa (90 mg, 0.94 mmol, 2.9 eq). After work-up the residue obtained was purified by Attorney Docket No.: 185992002240 Flash chromatography (12 g column, Eluent of 0 to 30% EtOAc/PE gradient at 20 mL/min) to afford D.1c (0.11 g, 0.18 mmol, 55% yield, 88% purity) as yellow oil. MS m/z (ESI) [M+H]+= 549.3. D.1d: tert-butyl 2-[2-[2-(azetidin-1-yl) thiazol-5-yl]-7-methoxy-4-quinolyl]-2,7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000345_0001
According to Scheme 5 Step 1: Conditions 4 Buchwald: To a solution of A.5c (0.10 g, 0.30 mmol, 1.0 eq) in dioxane (2.0 mL) was added tert-butyl 2,7-diazaspiro [4.5] decane-7- carboxylate (90 mg, 0.37 mmol, 1.2 eq), SPhos Pd G3 (25 mg, 32 μmol, 0.1 eq) and Cs2CO3 (0.30 g, 0.92 mmol, 3.1 eq). After work-up the crude product was purified by prep-TLC (PE/EtOAc = 3:1) to give D.1d (0.15 g, 0.24 mmol, 80% yield, 86% purity) as yellow oil. MS m/z (ESI) [M+H]+= 536.3. D.1e: tert-butyl 2-[2-[6-(dimethylamino) -3-pyridyl]-7-methoxy-4-quinolyl]-2, 7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000345_0002
According to Scheme 5 Step 1: Conditions 4 Buchwald: A.5a (0.10 g, 0.32 mmol, 1.0 eq), tert-butyl 2, 7-diazaspiro [4.5] decane-7-carboxylate (0.15 g, 0.62 mmol, 2.0 eq) in dioxane (2 mL), SPhos Pd G3 (0.1 eq), Cs2CO3 (2.0 eq). No work-up. The reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (PE/EtOAc = 1:1) to give D.1e (0.10 g, 0.17 mmol, 55% yield, 90% purity) as a white solid. Attorney Docket No.: 185992002240 D.1f: tert-butyl 2-[2-[2-(azetidin-1-yl)thiazol-5-yl]-7-(ethoxycarbonylamino)-4-quinolyl]- 3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridine-5-carboxylate
Figure imgf000346_0001
According to Scheme 5 Step 1: Conditions 4 Buchwald: To a solution of A.5k (120 mg, 315.22 μmol, 1 eq) in DMSO (0.5 mL) was added CsF (143.65 mg, 945.65 μmol, 3 eq) and tert-butyl 1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,4-c]pyridine-5-carboxylate (85.53 mg, 315.22 μmol, 1 eq, 0.5 oxalic acid). After work-up D.1f (100 mg, 157.74 μmol, 50.04% yield, 90% purity) was obtained as yellow oil. MS m/z (ESI) [M+H]+= 572.2. To a solution of tert-butyl 2-[2-[2-(azetidin-1-yl)thiazol-5-yl]-7-bromo-4-quinolyl]- 3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridine-5-carboxylate (100 mg, 175.27 μmol, 1 eq), ethyl carbamate (23.42 mg, 262.91 μmol, 1.5 eq) in dioxane (4 mL) was added t-BuONa (50.53 mg, 525.81 μmol, 3 eq) and BrettPhos Pd G3 (15.89 mg, 17.53 μmol, 0.1 eq). After work-up the residue was purified by prep-TLC (SiO2, DCM:MeOH = 10:1) to give D.1f (60 mg, 93.31 μmol, 53.24% yield, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 579.3. D.1g: 5- tert-butyl 2-[2-[6-(azetidin-1-yl)-3-pyridyl]-7-methoxy-4-quinolyl]-3,3a,4,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridine-5-carboxylate
Figure imgf000346_0002
According to Scheme 5 Step 1: To a solution of 2-[6-(azetidin-1-yl) -3-pyridyl]-4- chloro-7-methoxy-quinoline (250 mg, 767.36 μmol, 1 eq) in dioxane (5 mL) was added tert- butyl 1, 2, 3, 3a, 4, 6, 7, 7a-octahydropyrrolo[3, 4-c]pyridine-5-carboxylate (210 mg, 927.91 μmol, 1.21 eq), SPhos Pd G 3 (60 mg, 76.90 μmol, 0.1 eq) and Cs 2 CO 3 (750 mg, 2.30 mmol, 3 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 70~100% Ethyl acetate/Petroleum ether gradient Attorney Docket No.: 185992002240 @ 40 mL/min) to afford D.1g (250 mg, 460.59 μmol, 60.02% yield, 95% purity) as yellow oil. MS m/z (ESI) [M+H]+= 516.2. E.1a: tert-butyl 2-[2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-3-pyridyl]-6-fluoro-7- methoxy-4-quinolyl]-2,7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000347_0001
According to Scheme 5 Step 1: Conditions 2 Buchwald: C.1r (0.20 g, 0.42 mmol, 1.0 eq). After work-up the filtrate was concentrated in vacuo to give E.1a (0.20 g, 55% yield) as a white solid. MS m/z (ESI) [M+H]+= 677.6. E.1b: tert-butyl 2-[2-[6-[tert-butoxycarbonyl(methyl)amino]-3-pyridyl]-6-fluoro-7-methoxy- 4-quinolyl]-2,7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000347_0002
According to Scheme 5 Step 1: Conditions 1 Buchwald: C.1k (0.15 g, 0.36 mmol, 1.0 eq). After work-up the residue obtained was purified by Flash chromatography (12 g column, Eluent of 0~20% EtOAc/PE gradient at 40 mL/min) to afford E.1b (0.13 g, 0.21 mmol, 58% yield, 100% purity) as a light-yellow oil. MS m/z (ESI) [M+H]+= 622.3. E.1c: tert-butyl 2-(2-(4-(4-(tert-butoxycarbonyl) piperazin-1-yl) phenyl)-7-methoxyquinolin- 4-yl)-2,7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000347_0003
According to Scheme 5 Step 1: Conditions 1 Buchwald: C.1f (0.40 g, 0.88 mmol, 1.0 eq). Work-up was done and the combined organic layers were dried over Na2SO4 and evaporated to give a crude E.1c. MS m/z (ESI) [M+H]+= 658.4. Attorney Docket No.: 185992002240 E.1d: tert-butyl (cis)-2-(2-(4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)phenyl)-7- methoxyquinolin-4-yl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate
Figure imgf000348_0001
According to Scheme 5 Step 1: Conditions 1 Buchwald: C.1s (0.10 g, 0.23 mmol, 1.0 eq). After work-up E.1d (0.10 g, crude) was obtained as a yellow solid. MS m/z (ESI) [M+H]+= 633.4. E.1e: tert-butyl (cis)-2-[2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-3-pyridyl]-6-fluoro-7- methoxy-4-quinolyl]-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c] pyridine-5-carboxylate
Figure imgf000348_0002
According to Scheme 5 Step 1: Conditions 4 Buchwald: C.1r (0.10 g, 0.21 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-TLC (SiO2, PE/EtOAc = 0:1) to give E.1e (0.12 g, 0.16 mmol, 73% yield, 95% purity) as yellow gum. MS m/z (ESI) [M+H]+= 663.3. E.1f: tert-butyl 2-[2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-3-pyridyl]-7-(dimethylamino)- 6-fluoro-4-quinolyl]-2,7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000348_0003
According to Scheme 5 Step 1: Conditions 4 Buchwald: C.1l (0.20 g, 0.41 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-TLC (SiO2, EtOAc/MeOH = 10:1) to give E.1f (0.15 g, 0.17 mmol, 42% yield, 80% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 690.4. Attorney Docket No.: 185992002240 E.1g: tert-butyl (cis)-2-[2-[4-[2-[tert-butoxycarbonyl (methyl) amino]ethoxy]phenyl]-6- fluoro-7-methoxy-4-quinolyl]-3, 3a,4,6,7,7a-hexahydro-1H-pyrrolo[3, 4-c]pyridine-5- carboxylate
Figure imgf000349_0001
According to Scheme 5 Step 1: Conditions 2 Buchwald: C.1m (0.20 g, 0.43 mmol, 1.0 eq). After work-up the residue obtained was purified by silica gel chromatography (Biotage, 100-200 mesh silica gel) to afford E.1g (0.18 g, 0.28 mmol, 64% yield) as yellow solid. E.1h: tert-butyl 2-[2-[6-[4-[2-(tert-butoxycarbonylamino) propanoyl] piperazin-1-yl]-3- pyridyl]-7-methoxy-4-quinolyl]-2,7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000349_0002
According to Scheme 5 Step 1: Conditions 2 Buchwald: C.1q (0.23 g, 0.44 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-TLC (SiO2, PE/EtOAc = 0:1) to give E.1h (0.23 g, 0.28 mmol, 64% yield, 89% purity). MS m/z (ESI) [M+H]+= 730.4. E.1i: tert-butyl 2-[2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-3-pyridyl]-6-fluoro-7-methoxy- 4-quinolyl]-2,7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000349_0003
According to Scheme 5 Step 1: Conditions 2 Buchwald: C.1r (0.20 g, 0.42 mmol, 1.0 eq). After work-up the filtrate was concentrated in vacuo to give E.1i (200 mg, 55% yield) as a white solid. MS m/z (ESI) [M+H]+= 677.6. Attorney Docket No.: 185992002240 E.1j: tert-butyl 2-[2-[4-[4-[2-(tert-butoxycarbonylamino) propanoyl] piperazin-1-yl] phenyl]- 7-methoxy-4-quinolyl]-2,7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000350_0001
According to Scheme 5 Step 1: Conditions 4 Buchwald: C.1q (0.13 g, 0.25 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 30%-60% over 10 min) to give E.1j (80 mg, 0.11 mmol, 44% yield, 100% purity) was obtained as a yellow solid. MS m/z (ESI) [M+H]+= 729.4. E.1k: tert-butyl 4-[2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-3-pyridyl]-6-fluoro-7- methoxy-4-quinolyl]-1,4-diazepane-1-carboxylate
Figure imgf000350_0002
According to Scheme 5 Step 1: Conditions 4 Buchwald: C.1r (0.30 g, 0.63 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 30%-60% over 10 min). After Prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give E.1k (0.26 g, 0.21 mmol, 33% yield, 52% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 637.3. E.1l: tert-butyl (cis)-5-(2-(6-(4-(tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) quinolin- 4-yl) hexahydropyrrolo[3,4-c] pyrrole-2(1H)-carboxylate
Figure imgf000350_0003
According to Scheme 5 Step 1: Conditions 1 Buchwald: C.1a (0.25 g, 0.59 mmol, 1.0 eq), 120 °C for 72 h. After work-up the residue was purified by Flash chromatography (12g Attorney Docket No.: 185992002240 column, DCM/MeOH (100/0 to 60/40) to get E.1l (0.62 mg, 0.62 mmol, 60% purity, quant.) as yellow oil. MS m/z (ESI) [M+H]+= 601. E.1m: tert-butyl (1R,5S)-3-(2-(6-(4-(tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-3,6-diazabicyclo [3.2.0] heptane-6-carboxylate
Figure imgf000351_0001
According to Scheme 5 Step 1: Conditions 1 Buchwald: C.1a (0. 27 g, 0.64 mmol, 1.0 eq), 120 °C for 72 h. After work-up the residue was purified by Flash chromatography (12g column, DCM/MeOH (100/0 to 60/40) to get E.1m (0.50 g, 0.68 mmol, 80% purity, quant.) was obtained as a yellow oil. MS m/z (ESI) [M+H] += 587. E.1n: tert-butyl 6-(2-(6-(4-(tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)- 1,6-diazaspiro [3.4] octane-1-carboxylate
Figure imgf000351_0002
According to Scheme 5 Step 1: Conditions 1 Buchwald: C.1a (0.18 g, 0.42 mmol, 1.0 eq), 120 °C for 72 h. After work-up the residue was purified by Flash chromatography (12g column, DCM/MeOH (100/0 to 60/40) to get E.1n was obtained as a brown solid (0.41 g, 0.45 mmol, 65% purity, quant.) MS m/z (ESI) [M+H] += 601. E.1o: tert-butyl 7-(2-(6-(4-(tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)- 2,7-diazaspiro [4.4] nonane-2-carboxylate
Figure imgf000351_0003
Attorney Docket No.: 185992002240 According to Scheme 5 Step 1: Conditions 1 Buchwald: C.1a (0.18 g, 0.42 mmol, 1.0 eq), 120 °C for 72 h. After work-up the residue was purified by Flash chromatography (12g column, DCM/MeOH (100/0 to 60/40) to get E.1o (0.28 g, 0.45 mmol, quant.) was obtained as a yellow solid. MS m/z (ESI) [M+H] += 615. E.1p: tert-butyl (trans)-5-(2-(6-(4-(tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) hexahydropyrrolo[3,4-c] pyrrole-2(1H)-carboxylate
Figure imgf000352_0001
According to Scheme 5 Step 1: Conditions 1 Buchwald: C.1a (0.18 g, 0.42 mmol, 1.0 eq), 120 °C for 72 h. After work-up the residue was purified by Flash chromatography (12g column, DCM/MeOH (100/0 to 60/40) to get E.1p was obtained as a yellow solid (0.18 g, 0.30 mmol, 71%) MS m/z (ESI) [M+H] += 601. E.1q: tert-butyl (1R,5R)-6-(2-(6-(4-(tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-3,6-diazabicyclo [3.2.0] heptane-3-carboxylate
Figure imgf000352_0002
According to Scheme 5 Step 1: Conditions 1 Buchwald: C.1a (0.23 g, 0.54 mmol, 1.0 eq), 120 °C for 72 h. After work-up the residue was purified by Flash chromatography (12g column, DCM/MeOH (100/0 to 60/40) to get E.1q (0.16 g, 0.27 mmol, 51%) was obtained as a yellow oil. MS m/z (ESI) [M+H] += 587. Attorney Docket No.: 185992002240 E.1r: tert-butyl (1S,5R)-3-(2-(6-(4-(tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-3,6-diazabicyclo [3.2.0] heptane-6-carboxylate
Figure imgf000353_0001
According to Scheme 5 Step 1: Conditions 1 Buchwald: C.1a (0.27 g, 0.64 mmol, 1.0 eq), 120 °C for 72 h. No work-up. After work-up the residue was purified by prep-HPLC 6, and E.1r (0.11 g, 0.19 mmol, 30%) was obtained after lyophilization as a yellow powder. MS m/z (ESI) [M+H] += 587. E.1s: tert-butyl (cis)-6-(2-(6-(4-(tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) quinolin- 4-yl)-2,6-diazabicyclo [3.2.0] heptane-2-carboxylate
Figure imgf000353_0002
According to Scheme 5 Step 1: Conditions 1 Buchwald: C.1a (0.27 g, 0.64 mmol, 1.0 eq), 120 °C for 72 h. No work-up. After work-up the residue was purified by prep-HPLC 6 and E.1s (0.16 g, 0.27 mmol, 42%) was obtained after lyophilization as a yellow powder. MS m/z (ESI) [M+H] += 587. E.1t: tert-butyl 2-[2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-3-pyridyl]-7-methoxy-4- quinolyl]-2,7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000353_0003
According to Scheme 5 Step 1: Conditions 3 SNAr: C.1e (0.20 g, 0.44 mmol, 1.0 eq). After work-up the crude material was used in the next step without purification. E.1t (0.10 g, 0.13 mmol, 29% yield, 85% purity) was obtained as a white solid. MS m/z (ESI) [M+H] += 659.6. Attorney Docket No.: 185992002240 E.1u: tert-butyl 2-[2-[6-(1-tert-butoxycarbonylazetidin-3-yl)-3-pyridyl]-7-methoxy-4- quinolyl]-2,7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000354_0001
According to Scheme 5 Step 1: Conditions 3 SNAr: C.1g (0.15 g, 0.35 mmol, 1.0 eq). After work-up E.1u (0.41 g, crude) was obtained as brown solid. E.1v: tert-butyl 7-[2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-3-pyridyl]-7-methoxy-4- quinolyl]-2,7-diazaspiro [3.4] octane-2-carboxylate
Figure imgf000354_0002
According to Scheme 5 Step 1: Conditions 3 SNAr: C.1e (0.20 g, 0.44 mmol, 1.0 eq). After work-up E.1v (0.40 g, crude) was directly used into the next step without further purification as a brown gum. E.1w: tert-butyl 2-[7-bromo-2-[6-(methylamino) -3-pyridyl]-4-quinolyl]-2, 7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000354_0003
According to Scheme 5 Step 1: Conditions 1 SNAr: C.1p (0.28 g, 0.62 mmol, 1.0 eq). After work-up the residue obtained was purified by Flash chromatography (12 g column, Eluent of 80~100% EtOAc/PE gradient at 30 mL/min) to afford E.1w (0.30 g, 0.53 mmol, 85% yield, 98% purity) as yellow oil. 1H NMR (400 MHz, CDCl3) d (ppm): 7.38 - 7.33 (m, 5H), 5.14 (d, J = 4.9 Hz, 2H), 3.71 - 3.63 (m, 2H), 3.33 - 3.18 (m, 2H), 2.83 - 2.65 (m, 4H), 2.44 - 2.34 (m, 2H). MS m/z (ESI) [M+H]+= 450.0. Attorney Docket No.: 185992002240 E.1x: tert-butyl (cis)-2-(2-(4-(2-((tert-butoxycarbonyl) amino)-3-methylbutanamido) phenyl)- 6-fluoro-7-methoxyquinolin-4-yl) octahydro-5H-pyrrolo [3,4-c] pyridine-5-carboxylate
Figure imgf000355_0001
According to Scheme 5 Step 1: Conditions 4 Buchwald: C.1ab (0.29 g, 0.58 mmol, 1.0 eq), tert-butyl 1, 2, 3, 3a, 4, 6, 7, 7a-octahydropyrrolo [3, 4-c] pyridine-5-carboxylate oxalate (0.15 g, 0.55 mmol, 1.0 eq) in dioxane (4.0 mL), SPhos Pd G3 (0.10 eq), Cs2CO3 (3.2 eq). After work-up the residue obtained was purified by Flash chromatography (12 g column, Eluent of 0 to 100% EtOAc/PE gradient at 40 mL/min) to give E.1x (0.20 g, 0.28 mmol, 49% yield, 97% purity) as colorless gum. MS m/z (ESI) [M+H]+= 692.2. E.1y: tert-butyl (cis)-2-[2-[6-[4-[2-(tert-butoxycarbonylamino)-2-methyl-propanoyl] piperazin-1-yl]-3-pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-3,3a,4,6,7,7a-hexahydro-1H- pyrrolo[3,4-c] pyridine-5-carboxylate
Figure imgf000355_0002
According to Scheme 5 Step 1: Conditions 4 Buchwald: C.1ac (0.20 g, 0.36 mmol, 1.0 eq) in dioxane (10 mL), at 80 °C for 2 h. After work-up the residue obtained was purified by prep-TLC (PE/EtOAc = 1:1) to give E.1y (0.19 g, 0.20 mmol, 56% yield, 79% purity) as yellow oil. MS m/z (ESI) [M+H]+= 748.4. Attorney Docket No.: 185992002240 E.1z: tert-butyl 6-(2-(6-(4-(tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)- 2,6-diazaspiro [3.4] octane-2-carboxylate
Figure imgf000356_0001
According to Scheme 5 Step 1: Conditions 1 Buchwald: C.1a (0.25 g, 0.59 mmol, 1.0 eq), tert-butyl 2,7-diazaspiro [3.4]octane-2-carboxylate (0.25 g, 1.2 mmol, 2.0 eq), BrettPhos Pd G3 (0.10 eq), t-BuONa (1.2 eq), 120 °C for 12 h. After work-up the residue obtained was purified by Flash chromatography (12 g column, DCM/MeOH = 100:0 to 60:40) to give E.1z (0.41 g, 0.61 mmol, quant.). E.1aa: tert-butyl 2-[2-[6-[2-(tert-butoxycarbonylamino) propanoyl]-3-pyridyl]-6-fluoro-7- methoxy-4-quinolyl]-2,7-diazaspiro [4.5] decane-7-carboxylate.
Figure imgf000356_0002
According to Scheme 5 Step 1: Conditions 4 Buchwald: To a solution of C.1o (0.20 g, 0.43 mmol, 1.0 eq) and tert-butyl 2,7-diazaspiro [4.5] decane-7-carboxylate (0.18 g, 0.66 mmol, 1.5 eq, HCl) in dioxane (5.0 mL) was added SPhos-Pd-G3 (0.09 eq) and Cs2CO3 (4.1 eq). After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 29%-59% over 10 min). The eluent was lyophilized to give E.1aa (35 mg, 52 μmol, 12% yield, 98% purity) as a yellow gum. E.1ab: tert-butyl 7-(2-(6-(4-(tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) quinolin-4- yl)-2,7-diazaspiro [4.4] nonane-2-carboxylate
Figure imgf000356_0003
Attorney Docket No.: 185992002240 According to Scheme 5 Step 1: Conditions 4 Buchwald: C.1a (0.18 g, 0.42 mmol, 1.0 eq), SPhos-Pd-G3 (0.04 mmol), tert-butyl 2,7-diazaspiro [4.4]nonane-2-carboxylate;oxalic acid (0.27 g, 0.85 mmol, 2.0 eq) and sodium tert-butoxide (0.18 mL, 1.7 mmol, 4.0 eq), for 12 h at 120 °C. After work-up the residue obtained was purified by Flash chromatography (12 g column, DCM/MeOH 100:0 to 60:40) to give E.1ab (0.28 g, 0.45 mmol, quant.). E.1ac: tert-butyl 2-[2-[6-[2-[tert-butoxycarbonyl (methyl) amino]ethoxy]-3-pyridyl]-7- methoxy-4-quinolyl]-2, 7-diazaspiro[4.5]decane-7-carboxylate
Figure imgf000357_0001
According to Scheme 5 Step 1: Conditions 4 Buchwald: C.1ae (0.11 g, 0.29 mmol, 1.0 eq), tert-butyl 2, 7-diazaspiro [4.5] decane-7-carboxylate (89 mg, 0.32 mmol, 1.1 eq, HCl) and Cs2CO3 (2.0 eq) in 1, 4-dioxane (2.0 mL) was added SPhos Pd G3 (0.10 eq) at 20 °C. The reaction mixture was degassed and purged with N2 three times, and then the reaction mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC (SiO2, DCM/MeOH = 10:1) to give E.1ac (0.10 g, 0.15 mmol, 53% yield) was obtained as yellow oil. MS m/z (ESI) [M+H]+= 648.3. E.1ad: tert-butyl (cis)-2-[2-[6-[4-[2-(tert-butoxycarbonylamino) propanoyl] piperazin-1-yl]- 3-pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c] pyridine-5-carboxylate
Figure imgf000357_0002
According to Scheme 5 Step 1: Conditions 4 Buchwald: C.1x (0.23 g, 0.42 mmol, 1.0 eq), 1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,4-c] pyridine-5-carboxylate (0.12 g, 0.51 mmol, 1.2 eq), SPhos-Pd-G3 (0.10 eq) and Cs2CO3 (0.42 g, 1.3 mmol, 3.1 eq). After work-up the residue obtained was purified by Flash chromatography (40 g column, Eluent of 0 to 10% Attorney Docket No.: 185992002240 EtOAc/PE gradient at 40 mL/min) to afford E.1ad (0.30 g, 0.30 mmol, 71% yield, 73% purity) as red oil. MS m/z (ESI) [M+H]+= 734.2. E.1ae: tert-butyl 2-[2-[6-[2-(tert-butoxycarbonylamino) propanoyl]-3-pyridyl]-7- (dimethylamino)-6-fluoro-4-quinolyl]-2,7-diazaspiro [4.5] decane-7-carboxylate
Figure imgf000358_0001
According to Scheme 5 Step 1: Conditions 4 Buchwald: To a mixture of C.1y (80 mg, 0.17 mmol, 1.0 eq), tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate (50 mg, 0.21 mmol, 1.2 eq) in dioxane (3.0 mL) was added SPhos Pd G3 (0.10 eq) and Cs2CO3 (3.0 eq) at 25°C. After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 30%-60% over 10 min) to give E.1ae (50 mg, 70 μmol, 41% yield, 95% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 677.4. E.1af: tert-butyl (cis)-2-[2-[6-[2-[tert-butoxycarbonyl (methyl) amino]ethoxy]-3-pyridyl]-6- fluoro-4-quinolyl]-3, 3a, 4, 6, 7, 7a-hexahydro-1H-pyrrolo[3, 4-c]pyridine-5-carboxylate
Figure imgf000358_0002
According to Scheme 5 Step 1: Conditions 4 Buckwald: C.1z (0.30 g, 0.57 mmol, 1.0 eq) and tert-butyl 1, 2, 3, 3a, 4, 6, 7, 7a-octahydropyrrolo [3, 4-c] pyridine-5-carboxylate (0.15 g, 0.55 mmol, 0.98 eq, 0.5 oxalic acid) in dioxane (7.0 mL). After work-up the residue obtained was purified by Flash chromatography (4 g column, Eluent of 0 to 100% EtOAc/PE gradient at 20 mL/min) to give E.1af (0.19 mg, 0.25 mmol, 44% yield, 84% purity) as colorless gum. MS m/z (ESI) [M+H]+= 622.4. Attorney Docket No.: 185992002240 E.1ag: tert-butyl (cis)-2-[2-[6-[2-[tert-butoxycarbonyl (methyl) amino]ethoxy]-3-pyridyl]-6, 7-difluoro-4-quinolyl]-3, 3a, 4, 6, 7, 7a-hexahydro-1H-pyrrolo[3, 4-c]pyridine-5-carboxylate
Figure imgf000359_0001
According to Scheme 5 Step 1: Conditions 4 Buchwald: To a solution of C.1aa (0.18 g, 0.40 mmol, 1.0 eq), tert-butyl 1, 2, 3, 3a, 4, 6, 7, 7a-octahydropyrrolo [3, 4-c] pyridine-5- carboxylate (0.10 g, 0.44 mmol, 1.1 eq) in dioxane (5.0 mL) were added SPhos Pd G3 (0.10 eq) and Cs2CO3 (2.3 eq). After work-up the residue obtained was purified by prep-TLC (PE/EtOAc = 0:1) to give E.1ag (0.15 g, 0.20 mmol, 50% yield, 85% purity) as a yellow solid. E.1ah: tert-butyl 2-[2-[6-[tert-butoxycarbonyl (methyl) amino]-3-pyridyl]-7-chloro-4- quinolyl]-2, 7-diazaspiro[4.5]decane-7-carboxylate
Figure imgf000359_0002
According to Scheme 5 Step 1: Conditions 2 Buchwald: To a solution of C.1ad (0.20 g, 0.49 mmol, 1.0 eq), tert-butyl 2, 7-diazaspiro [4.5] decane-7-carboxylate (1.5 eq) in dioxane (3.0 mL) were added Pd(t-Bu3P)2 (30 mg, 59 μmol, 0.12 eq) and t-BuONa (2.1 eq). After work-up the residue obtained was purified by prep-TLC (PE/EtOAc = 0:1) to give E.1ah (0.15 g, 0.18 mmol, 37% yield, 75% purity) as a white solid. E.1ai: tert-butyl (1S,5S)-6-[2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-3-pyridyl]-4- quinolyl]-3,6-diazabicyclo [3.2.0] heptane-3-carboxylate
Figure imgf000359_0003
Attorney Docket No.: 185992002240 According to Scheme 5 Step 1: Conditions 1 Buchwald: C.1a (0.27 g, 0.64 mmol, 1.0 eq), tert-butyl (1S,5S)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (0.25 g, 1.3 mmol, 2.0 eq) [cis-pure], BrettPhos Pd G4 (0.10 eq) and sodium tert-butoxide (0.13 mL, 1.3 mmol, 2.0 eq). After work-up the residue obtained was purified by prep-HPLC 5 to give E.1ai (75 mg, 0.13 mmol, 20%) as a yellow powder. E.1aj: tert-butyl 2-[2-[4-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-6-fluoro-7- (trideuteriomethoxy)-4-quinolyl]-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridine-5- carboxylate
Figure imgf000360_0001
According to Scheme 6 Step 1: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-[4-chloro-6-fluoro-7-(trideuteriomethoxy)-2-quinolyl]phenoxy]ethyl]-N-methyl- carbamate (260 mg, 560.41 μmol, 1 eq) in dioxane (10 mL) was added tert-butyl 1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,4-c]pyridine-5-carboxylate (150 mg, 662.79 μmol, 1.18 eq), SPhos Pd G3 (50 mg, 64.08 μmol, 1.14e-1 eq) and Cs2CO3 (550 mg, 1.69 mmol, 3.01 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to E.1aj (350 mg, 518.74 μmol, 92.56% yield, 96.9% purity) as yellow oil. MS m/z (ESI) [M+H]+= 654.3. E.1aq: tert-butyl 2-[2-[4-[2-(tert-butoxycarbonylamino)propanoyl]phenyl]-7- (dimethylamino)-6-fluoro-4-quinolyl]-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridine-5- carboxylate
Figure imgf000360_0002
Attorney Docket No.: 185992002240 According to Scheme 6 Step 1: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-[4-chloro-7-(dimethylamino)-6-fluoro-2-quinolyl]phenyl]-1-methyl-2-oxo- ethyl]carbamate (150 mg, 317.83 μmol, 1 eq), tert-butyl 1,2,3,3a,4,6,7,7a- octahydropyrrolo[3,4-c]pyridine-5-carboxylate (107.89 mg, 476.74 μmol, 1.5 eq) in dioxane (4 mL) was added SPhos Pd G3 (24.80 mg, 31.78 μmol, 0.1 eq) and Cs2CO3 (310.67 mg, 953.49 μmol, 3 eq). After work-up the residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate= 1:1) to give E.1aq (120 mg, 163.19 μmol, 51.35% yield, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 662.2. E.1ar: tert-butyl2-[2-[4-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-6-fluoro-7- pent-4-ynoxy-4-quinolyl]-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridine-5-carboxylate
Figure imgf000361_0001
Step 1: According to Scheme 6 Step 1: Conditions 3 Buchwald: To a solution of tert- butyl N-[2-[4-[4-chloro-6-fluoro-7-(5-trimethylsilylpent-4-ynoxy)-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate (250 mg, 427.22 μmol, 1 eq) in dioxane (4 mL) was added tert-butyl 1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,4-c]pyridine-5-carboxylate (120 mg, 530.24 μmol, 1.24 eq), Cs2CO3 (450 mg, 1.38 mmol, 3.23 eq), SPhos Pd G3 (40 mg, 51.27 μmol, 0.12 eq). After work-up the crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give tert-butyl 2-[2-[4-[2-[tert- butoxycarbonyl(methyl)amino]ethoxy]phenyl]-6-fluoro-7-(5-trimethylsilylpent-4-ynoxy)-4- quinolyl]-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridine-5-carboxylate (200 mg, 229.67 μmol, 53.76% yield, 89% purity) a yellow solid. MS m/z (ESI) [M+H]+= 755.4. Step2: To a solution of tert-butyl 2-[2-[4-[2-[tert- butoxycarbonyl(methyl)amino]ethoxy]phenyl]-6-fluoro-7-(5-trimethylsilylpent-4-ynoxy)-4- quinolyl]-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridine-5-carboxylate (150 mg, 193.54 μmol, 1 eq) in MeOH (2 mL) was added K2CO3 (70 mg, 506.49 μmol, 2.62 eq), then the resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered to give Attorney Docket No.: 185992002240 the crude product. The crude product evaporated under reduced pressure to give E.1ar (140 mg, crude) as a yellow solid. MS m/z (ESI) [M+H]+= 703.3. E.1as: tert-butyl 2-[2-[4-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-6-fluoro-7- methoxy-4-quinolyl]-2,7-diazaspiro[4.5]decane-7-carboxylate
Figure imgf000362_0001
According to Scheme 6 Step 1: Conditions 3 Buchwald: To a solution of tert-butyl N- [2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl) phenoxy]ethyl]-N-methyl-carbamate (200 mg, 433.91 μmol, 1 eq) in dioxane (10 mL) was added tert-butyl 2, 7-diazaspiro[4.5]decane- 7-carboxylate (145 mg, 523.84 μmol, 1.21 eq, HCl), Cs2CO3 (425 mg, 1.30 mmol, 3.01 eq) and SPhos Pd G3 (35 mg, 44.86 μmol, 1.03e-1 eq). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to afford E.1as (222 mg, 330.59 μmol, 76.19% yield, 99% purity) as yellow oil. MS m/z (ESI) [M+H]+= 665.5. E.1at: tert-butyl 2-[2- (tert-butoxycarbonylamino) -2-methyl-propanoyl]amino]-3-
Figure imgf000362_0002
pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-3, 3a, 4, 6, 7, 7a-hexahydro-1H-pyrrolo[3, 4- c]pyridine-5-carboxylate
Figure imgf000362_0003
According to Scheme 6 Step 1: Conditions 3 Buchwald: To a screw-cap vial equipped with a magnetic stir bar was added tert-butyl N-[2-[[5-(4-chloro-6-fluoro-7-methoxy-2- quinolyl) -2-pyridyl]amino]-1, 1-dimethyl-2-oxo-ethyl]carbamate (80 mg, 163 μmol, 1 eq) and dioxane (1.5 mL) and tert-butyl 1, 2, 3, 3a, 4, 6, 7, 7a-octahydropyrrolo[3, 4-c]pyridine- 5-carboxylate oxalate (50 mg, 184.28 μmol, 1.13 eq) and Cs2CO3 (160 mg, 491 μmol, 3 eq) and SPhos Pd G3 (15 mg, 19.2 μmol, 0.1 eq) sequentially. After work-up the residue was purified by prep-TLC (Petroleum ether/Ethylacetate=0/1, Rf=0.43) to give E.1at (30 mg, 44.2 μmol, 27% yield) as yellow solid. Attorney Docket No.: 185992002240 E.1au: tert-butyl 2-[2-[4-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-6-fluoro-7- (trideuteriomethoxy)-4-quinolyl]- 7-carboxylate
Figure imgf000363_0001
According to Scheme 6 Step 1: Conditions 3 Buchwald: A mixture of tert-butyl N-[2- [4-[4-chloro-6-fluoro-7-(trideuteriomethoxy)-2-quinolyl]phenoxy]ethyl]-N-methyl-carbamate (200 mg, 431.09 μmol, 1 eq), tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate (124.33 mg, 517.30 μmol, 1.2 eq), SPhos Pd G3 (33.64 mg, 43.11 μmol, 0.1 eq), Cs2CO3 (421.37 mg, 1.29 mmol, 3 eq) in dioxane (2 mL). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 40mL/min) to give E.1au (200 mg, 299.48 μmol, 69.47% yield, 100% purity) as yellow oil. MS m/z (ESI) [M+H]+= 668.4. E.1av: tert-butyl cis-2-(2-(4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)phenyl)-7- methoxyquinolin-4-yl)-4-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate
Figure imgf000363_0002
According to Scheme 6 Step 1: Condition 4 Buckwald: A mixture of tert-butyl N-[2- [4-(4-chloro-7-methoxy-2-quinolyl)phenoxy]ethyl]-N-methyl-carbamate (300 mg, 677.30 μmol, 1 eq), tert-butyl cis-4-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (325.51 mg, 1.35 mmol, 2 eq), SPhos Pd G3 (52.85 mg, 67.73 μmol, 0.1 eq), Cs2CO3 (662.03 mg, 2.03 mmol, 3 eq) in dioxane (3 mL). After work-up the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 40mL/min) to give E.1av (200 mg, 240.37 μmol, 35.49% yield, 65.7% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 547.3. Synthesis of final products Final products from Suzuki coupling (Scheme 2; Step 2), Buchwald coupling or SNAr (Scheme 1; step 5) – See above protocols. Final products from deprotection step (Scheme 3; Step 3), (Schemes 4, 5 and 6; Step 2) – See protocols below. Attorney Docket No.: 185992002240 Conditions 1 HCl: To a solution of substrate C.2 or D.1 or E.1 (1.0 eq) in dioxane (0.06M) was added HCl/dioxane (> 20 eq). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to give a residue. Purifications described below. Conditions 2 TFA: To a solution of substrate C.2 or D.1 or E.1 (1.0 eq) in DCM (0.15M) was added TFA (> 10 eq) at 25 °C. After stirring at 25 °C for 4 h, the reaction mixture was filtered and concentrated under reduced pressure. Purifications described below. Conditions 3 TMSOTf: To a solution of substrate C.2 or D.1 or E.1 (1.0 eq) in DCM (0.15M) was added TMSOTf (> 3 eq) and 2,6-dimethylpyridine (>9 eq) at 0°C. After stirring at 0°C for 0.5 hours, the reaction mixture was concentrated under reduced pressure to give a residue at 25°C. Purifications described below. Example 1: 1-(4-(5-(6,7-dimethoxy-4-(pyrrolidin-1-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one
Figure imgf000364_0001
According to Scheme 1 Step 5: Conditions 3 SNAr with substrate A.5i (0.10 g, 0.23 mmol, 1.0 eq). After work-up the crude product was triturated with MeOH (10 mL) at 25 °C for 20 min to give Example 1 (32 mg, 68 μmol, 29% yield, 99% purity) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (d, J = 1.2 Hz, 1H), 8.37 - 8.28 (m, 1H), 7.49 (s, 1H), 7.24 (s, 1H), 7.00 - 6.88 (m, 2H), 3.89 (d, J = 12 Hz, 6H), 3.70 (s, 4H), 3.65 (d, J = 2.7 Hz, 2H), 3.57 (s, 6H), 2.06 (s, 3H), 1.99 (s, 4H). MS m/z (ESI) [M+H]+= 462.2. Example 2: (1-(2-(6-(azetidin-1-yl) pyridin-3-yl)-6-fluoro-7-methoxyquinolin-4-yl) pyrrolidin-3-yl) methanol
Figure imgf000364_0002
According to Scheme 1 Step 5: Conditions 4 Buchwald with substrate A.5b (0.10 mg, 0.29 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 7 (gradient: 30%-50% over 8 min) to give Example 2 (84 mg, 0.21 mmol, 71% yield, 100% Attorney Docket No.: 185992002240 purity), which was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.86 (d, J = 2.0 Hz, 1H), 8.27 (dd, J = 2.4, 8.8 Hz, 1H), 7.94 (d, J = 14 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.83 (s, 1H), 6.42 (d, J = 8.6 Hz, 1H), 4.75 (t, J = 5.4 Hz, 1H), 4.01 (t, J = 7.6 Hz, 4H), 3.97 (s, 3H), 3.73 - 3.68 (m, 2H), 3.58 - 3.43 (m, 4H), 2.47 - 2.40 (m, 1H), 2.39 - 2.32 (m, 2H), 2.09 - 2.01 (m, 1H), 1.80 - 1.72 (m, 1H). MS m/z (ESI) [M+H]+= 409.2. Example 3: 2-(4-(5-(6-fluoro-4-(3-(hydroxymethyl) pyrrolidin-1-yl)-7-methoxyquinolin-2- yl) pyridin-2-yl) piperazin-1-yl) ethan-1-ol
Figure imgf000365_0001
According to Scheme 1 Step 5: Conditions 4 Buchwald with substrate C.1v (0.10 g, 0.19 mmol, 1.0 eq), only 3 h. After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 15%-45% over 10 min) to give pure product. The residue was further purified by SCX (see general protocol) to give Example 3 (39 mg, 80 μmol, 42% yield, 98% purity) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.69 (d, J = 2.3 Hz, 1H), 8.12 (dd, J = 2.5, 9.0 Hz, 1H), 8.01 (d, J = 14 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 6.73 (s, 1H), 4.02 (s, 3H), 3.86 - 3.65 (m, 12H), 2.70 - 2.66 (m, 4H), 2.61 (t, J = 5.9 Hz, 2H), 2.59 - 2.54 (m, 1H), 2.23 - 2.10 (m, 1H), 1.94 - 1.85 (m, 1H). MS m/z (ESI) [M+H]+= 482.3. Example 4: (1-(2-(2-(azetidin-1-yl) thiazol-5-yl)-6-fluoro-7-methoxyquinolin-4-yl) pyrrolidin-3-yl) methanol
Figure imgf000365_0002
According to Scheme 1 Step 5: Conditions 1 Buchwald with substrate A.5f (40 mg, 80 μmol, 1.0 eq). The reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, DCM: MeOH = 10:1) to give the crude product. The crude product was purified by prep-HPLC 7 (gradient: 34%-54% over 8 min) to give Example 4 (1.9 mg, 4.5 μmol, 5.7% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.94 (s, 1H), 7.91 (d, J = 14 Hz, 1H), 7.23 (d, J = 9.0 Attorney Docket No.: 185992002240 Hz, 1H), 6.82 (s, 1H), 4.75 (t, J = 5.3 Hz, 1H), 4.06 (t, J = 7.5 Hz, 4H), 3.95 (s, 3H), 3.61 - 3.78 (m, 3H), 3.44 - 3.59 (m, 3H), 2.36 - 2.48 (m, 3H), 2.05 (dq, J = 12, 6.1 Hz, 1H), 1.65 - 1.85 (m, 1H). MS m/z (ESI) [M+H]+ = 415.1. Example 5: (1-(2-(6-(azetidin-1-yl) pyridin-3-yl)-7-(dimethylamino)-6-fluoroquinolin-4-yl) pyrrolidin-3-yl) methanol
Figure imgf000366_0001
According to Scheme 1 Step 5: Conditions 1 Buchwald with substrate A.5g (0.12 g, 0.34 mmol, 1.0 eq). The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by prep-TLC (SiO2, DCM/MeOH = 10:1) to give the crude product. The crude product was purified by prep-HPLC 7 (gradient: 34%-54% over 8 min) to give Example 5 (22 mg, 52 μmol, 15% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.83 (d, J = 2.1 Hz, 1H), 8.25 (dd, J = 8.7, 1.9 Hz, 1H), 7.85 (d, J = 16 Hz, 1H), 7.17 (d, J = 9.5 Hz, 1H), 6.77 (s, 1H), 6.42 (d, J = 8.8 Hz, 1H), 4.69 (t, J = 5.3 Hz, 1H), 4.02 (t, J = 7.3 Hz, 4H), 3.64 - 3.82 (m, 3H), 3.42 - 3.61 (m, 3H), 2.93 (s, 6H), 2.41 - 2.46 (m, 1H), 2.31 - 2.39 (m, 2H), 2.06 (dq, J = 12, 6.1 Hz, 1H), 1.69 - 1.85 (m, 1H). MS m/z (ESI) [M+H]+ = 422.3. Example 6: (cis)-2-(2-(6-(dimethylamino) pyridin-3-yl)-7-methoxyquinolin-4-yl) octahydro- 6H-pyrrolo[3,4-c] pyridin-6-one
Figure imgf000366_0002
According to Scheme 1 Step 5: Conditions 1 Buchwald with substrate A.5a (0.10 g, 0.32 mmol, 1.0 eq) and amine.1. After work-up the residue obtained was purified by prep- HPLC 2 (gradient: 6%-26% over 10 min) then the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give Example 6 (7 mg, 16.77 μmol, 5.26% yield, 100% purity) as a white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): Attorney Docket No.: 185992002240 8.68 (d, J = 2.4 Hz, 1H), 8.52 (s, 1H), 8.40 (d, J = 9.5 Hz, 1H), 8.08 (dd, J = 2.6, 9.1 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.18 (dd, J = 2.6, 9.5 Hz, 1H), 6.83 (d, J = 9.1 Hz, 1H), 6.79 (s, 1H), 4.24 - 4.13 (m, 2H), 3.99 (s, 3H), 3.93 - 3.84 (m, 2H), 3.57 (dd, J = 5.8, 13 Hz, 1H), 3.39 (dd, J = 6.1, 13 Hz, 1H), 3.20 (s, 6H), 3.00 - 2.91 (m, 1H), 2.91 - 2.82 (m, 1H), 2.66 (dd, J = 7.6, 18 Hz, 1H), 2.37 (dd, J = 5.6, 18 Hz, 1H). MS m/z (ESI) [M+H]+ = 418.2. Example 7: 6,7-dimethoxy-2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(pyrrolidin-1-yl) quinoline
Figure imgf000367_0001
According to Scheme 3 Step 3: Conditions 1 HCl with substrate C.2e (0.40 g, 0.77 mmol, 1.0 eq). TAftert work-up the residue obtained was purified by prep-HPLC 7 (gradient: 15%-45% over 10 min), followed by lyophilization to give Example 7 (0.17 g, 0.40 mmol, 52% yield, 99% purity) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) : 8.88 (d, J = 2.3 Hz, 1H), 8.29 (dd, J = 2.5, 9.0 Hz, 1H), 7.47 (s, 1H), 7.23 (s, 1H), 6.90 (s, 1H), 6.87 (d, J = 8.9 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.75 - 3.64 (m, 4H), 3.53 - 3.45 (m, 4H), 2.85 - 2.75 (m, 4H), 2.06 - 1.92 (m, 4H). MS m/z (ESI) [M+H]+= 420.3. Example 8: 2-(4-(5-(6,7-dimethoxy-4-(pyrrolidin-1-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-ol
Figure imgf000367_0002
According to Scheme 3 Step 3: Conditions 1 HCl with substrate C.2f (70 mg, 0.12 mmol, 1.0 eq). The reaction mixture was concentrated under reduced pressure to give a crude product purified with SCX (see general protocol). Example 8 (40 mg, 86 μmol, 86% yield, 99% purity) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.87 (d, J = 2.4 Hz, 1H), 8.28 (dd, J = 2.4, 8.9 Hz, 1H), 7.49 (s, 1H), 7.25 (s, 1H), 6.94 - 6.87 (m, 2H), 4.46 (d, J = 1.1 Hz, 1H), 3.89 (d, J = 11 Hz, 6H), 3.71 (s, 4H), 3.57 (d, J = 4.6 Hz, 6H), 2.54 (d, J = 5.1 Hz, 4H), 2.47 - 2.43 (m, 2H), 1.99 (s, 4H). MS m/z (ESI) [M+H]+= 464.2. Attorney Docket No.: 185992002240 Example 9: 1-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-3- methylpyrrolidin-3-ol
Figure imgf000368_0001
According to Scheme 3 Step 3: Conditions 1 HCl with substrate C.2g (0.10 g, 0.19 mmol, 1.0 eq) in MeOH (1.0 mL). After work-up the residue obtained was purified by prep- HPLC 8 (gradient: 6%-36% over 8 min). Then the product was further purified with SCX (see general protocol). Example 9 (19 mg, 45 μmol, 24% yield, 100% purity) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) : 8.93 (d, J = 2.4 Hz, 1H), 8.36 - 8.30 (m, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 6.95 - 6.87 (m, 2H), 6.82 - 6.77 (m, 1H), 4.86 (br s, 1H), 3.99 - 3.92 (m, 1H), 3.8 (s, 3H), 3.81 (br d, J = 10.4 Hz, 1H), 3.66 - 3.61 (m, 1H), 3.58 - 3.52 (m, 5H), 2.90 - 2.79 (m, 4H), 2.01 - 1.86 (m, 2H), 1.40 (s, 3H). MS m/z (ESI)[M+H]+= 420.2. Example 10: (1-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) pyrrolidin-3- yl) methanol
Figure imgf000368_0002
According to Scheme 3 Step 3: Conditions 1 HCl with substrate C.2m (0.10 g, 0.19 mmol, 1.0 eq) in MeOH (5.0 mL). After work-up the residue obtained was purified by prep- HPLC 2 (gradient: 5%-35% over 8 min). Then the crude product was further purified with SCX (see general protocol). Example 10 (47 mg, 0.11 mmol, 57% yield, 98% purity) was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (d, J = 2.4 Hz, 1H), 8.31 (dd, J = 8.8, 2.4 Hz, 1H) 8.14 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 6.97 - 6.80 (m, 3H), 4.74 (br s, 1H), 3.88 (s, 3H), 3.78 - 3.65 (m, 3H), 3.59 - 3.65 (m, 7H), 2.86 - 2.76 (m, 4H), 2.47 - 2.39 (m, 1H), 2.06 (dq, J = 11.6, 6.0 Hz, 1H), 1.77 (dq, J = 12.4, 8.0 Hz, 1H). MS m/z (ESI) [M+H] += 420.3. Attorney Docket No.: 185992002240 Example 11: 2-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-2,7-diazaspiro [4.5] decane
Figure imgf000369_0001
According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.1t (0.10 g, 0.15 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 2%-30% over 8 min). Example 11 (59 mg, 0.13 mmol, 84% yield, 100% purity) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.92 (d, J = 1.6 Hz, 1H), 8.32 (dd, J = 8.8, 2.0 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 6.98 - 6.81 (m, 3H), 3.88 (s, 3H), 3.84 - 3.75 (m, 1H), 3.73 - 3.63 (m, 2H), 3.56 - 3.53 (m, 1H), 3.51 (br s, 4H), 2.80 (br s, 4H), 2.76 - 3.53 (m, 4H), 2.02 - 1.87 (m, 1H), 1.84 - 1.44 (m, 5H). MS m/z (ESI) [M+H]+= 459.4. Example 12: 4-(2-methylpyrrolidin-1-yl)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline
Figure imgf000369_0002
According to Scheme 3 Step 3: Conditions 2 TFA with subtrate C.2o (0.16 mg, 0.33 mmol, 1.0 eq), TFA (26 eq). After work-up the reaction mixture was concentrated and purified by prep-HPLC 6 to give after lyophilization Example 12 (0.13 g, 0.35 mmol, quant.) as a yellow fluffy powder. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.80 (d, J = 2.5 Hz, 1H), 8.47 (d, J = 7.3 Hz, 1H), 8.21 (dd, J = 8.9, 2.7 Hz, 1H), 7.98 (dd, J = 8.5, 1.4 Hz, 1H), 7.88 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.61 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.13 (d, J = 8.9 Hz, 1H), 6.96 (s, 1H), 4.60 (h, J = 6.5 Hz, 1H), 4.37 – 4.26 (m, 1H), 4.07 (m, 1H), 4.01 – 3.95 (m, 4H), 3.37 – 3.30 (m, 5H), 2.49 – 2.38 (m, 1H), 2.23 (m, 1H), 2.04 – 1.86 (m, 2H), 1.47 (d, J = 6.2 Hz, 3H). MS m/z (ESI) [M+H]+= 374.20. Attorney Docket No.: 185992002240 Example 13: 2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(pyrrolidin-1-yl) quinoline
Figure imgf000370_0001
According to Scheme 3 Step 3: Conditions 2 TFA with substrate C.2p (0.16 g, 0.35 mmol, 1.0 eq), TFA (25 eq) was added. After work-up the residue obtained was purified by prep-HPLC 6 to give after lyophilization Example 13 (50 mg, 0.14 mmol, 40%) as a yellow fluffy powder. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.80 (d, J = 2.5 Hz, 1H), 8.58 (d, J = 7.8 Hz, 1H), 8.21 (dd, J = 9.0, 2.6 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.88 (t, J = 7.7 Hz, 1H), 7.62 (t, J = 7.1 Hz, 1H), 7.11 (d, J = 9.1 Hz, 1H), 6.89 (s, 1H), 4.07 (s, 4H), 3.99 – 3.92 (m, 4H), 3.34 – 3.24 (m, 4H), 2.26 – 2.15 (m, 4H). MS m/z (ESI) [M+H]+= 360.20. Example 14: 2-(2-(6-(azetidin-3-yl) pyridin-3-yl)-7-methoxyquinolin-4-yl)-2,7-diazaspiro [4.5] decane
Figure imgf000370_0002
According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.1u (0.41 g, 0.65 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 1%-20% over 10 min). After Prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give Example 14 (33 mg, 77 μmol, 12% yield, 99% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.35 (d, J = 1.8 Hz, 1H), 8.49 (dd, J = 2.1, 8.1 Hz, 1H), 8.24 (d, J = 9.4 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.01 (dd, J = 2.8, 9.4 Hz, 1H), 6.95 (s, 1H), 4.18 (br s, 1H), 4.07 - 3.94 (m, 4H), 3.91 (s, 3H), 3.86 - 3.81 (m, 1H), 3.75 (br d, J = 9.5 Hz, 2H), 3.58 - 3.55 (m, 2H), 2.75 - 2.55 (m, 5H), 2.02 - 1.95 (m, 1H), 1.82 - 1.75 (m, 1H), 1.52 (br s, 4H). MS m/z (ESI) [M+H]+= 430.2. Attorney Docket No.: 185992002240 Example 15: 6-methoxy-4-(3-methoxypyrrolidin-1-yl)-N, N-dimethyl-2-(4-(2-(methylamino) ethoxy) phenyl) quinolin-7-amine
Figure imgf000371_0001
According to Scheme 3 Step 3: Conditions 1 HCl with substrate C.2j (0.10 g, 0.18 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 8%-38% over 9 min) to give pure product. Then the residue was further purified with SCX (see general protocol) to give Example 15 (45 mg, 97 μmol, 53% yield, 98% purity) as yellow gum. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.10 (d, J = 8.8 Hz, 2H), 7.41 (s, 1H), 7.16 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.89 (s, 1H), 4.12 - 4.07 (m, 3H), 3.95 (d, J = 4.6 Hz, 1H), 3.92 (s, 3H), 3.85 - 3.78 (m, 1H), 3.65 - 3.60 (m, 2H), 3.29 (s, 3H), 2.89 (t, J = 5.6 Hz, 2H), 2.85 (s, 6H), 2.37 (s, 3H), 2.15 - 2.06 (m, 2H). MS m/z (ESI) [M+H]+= 451.2. Example 16: 4-(3-methoxypyrrolidin-1-yl)-N, N-dimethyl-2-(6-(2-(methylamino) ethoxy) pyridin-3-yl) quinolin-7-amine
Figure imgf000371_0002
According to Scheme 3 Step 3: Conditions 1 HCl with substrate C.2l (0.10 g, 0.19 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 5%-35% over 9 min) to give (4-(3-methoxypyrrolidin-1-yl)-N, N-dimethyl-2-[6-[2- (methylamino) ethoxy]-3-pyridyl] quinolin-7-amine (HCl salt)). Then the salt was purified with SCX (see general protocol) to give Example 16 (34 mg, 81 μmol, 42% yield, 100% purity) as a yellow gum. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (d, J = 2.2 Hz, 1H), 8.46 (dd, J = 8.7, 2.5 Hz, 1H), 8.07 (d, J = 9.4 Hz, 1H), 6.85 - 7.06 (m, 3H), 6.75 (s, 1H), 4.37 (t, J = 5.8 Hz, 2H), 4.10 (d, J = 2.1 Hz, 1H), 3.93 (dd, J = 11, 4.4 Hz, 1H), 3.76 - 3.86 (m, 1H), 3.58 - 3.71 (m, 2H), 3.28 (s, 3H), 3.03 (s, 6H), 2.88 (t, J = 5.7 Hz, 2H), 2.36 (s, 3H), 2.01 - 2.17 (m, 2H). MS m/z (ESI) [M+H]+= 422.2. Attorney Docket No.: 185992002240 Example 17: 2-(6-fluoro-7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-2,7- diazaspiro [4.5] decane
Figure imgf000372_0001
According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.1a (0.20 g, 0.30 mmol, 1.0 eq) in methanol (1.0 mL). After work-up the residue obtained was purified by prep-HPLC 3 (gradient: 10%-40% over 10 min) and then prep-HPLC 8 (gradient: 1%-30% over 9 min) to give Example 17 (51 mg, 36% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.85 (s, 1H), 8.60 (d, J = 4.4 Hz, 1H), 8.32 (d, J = 13.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 6.96 (s, 1H), 4.26-4.22 (m, 3H), 4.16 (t, J = 5.2 Hz, 4H), 4.10 (s, 3H), 4.09-4.07 (m, 1H), 3.52 (t, J = 5.2 Hz, 4H), 3.32-3.19 (m, 4H), 2.29-2.17 (m, 2H), 2.00-1.63 (m, 4H). MS m/z (ESI) [M+H]+= 477.4. Example 18: (1-(6-fluoro-7-methoxy-2-(6-(methylamino) pyridin-3-yl) quinolin-4-yl) pyrrolidin-3-yl) methanol
Figure imgf000372_0002
According to Scheme 3 Step 3: Conditions 1 HCl with substrate C.2b (50 mg, 0.10 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 4%-34% over 10 min). After prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give Example 18 (8.3 mg, 21 μmol, 20% yield, 98% purity) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.55 (d, J = 1.8 Hz, 1H), 8.52 (br s, 1H), 8.18 (d, J = 13 Hz, 1H), 8.00 - 7.89 (m, 1H), 7.46 (br d, J = 8.1 Hz, 1H), 6.70 (s, 1H), 6.66 (d, J = 8.8 Hz, 1H), 4.08 - 3.95 (m, 6H), 3.80 (br dd, J = 8.1, 11 Hz, 1H), 3.76 - 3.70 (m, 1H), 3.69 - 3.62 (m, 1H), 2.96 - 2.96 (m, 1H), 2.96 (s, 2H), 2.67 - 2.58 (m, 1H), 2.25 (qd, J = 5.9, 11.6 Hz, 1H), 2.00 - 1.89 (m, 1H). MS m/z (ESI) [M+H]+= 383.2. Attorney Docket No.: 185992002240 Example 19: 5-(6-fluoro-7-methoxy-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-2-yl)-N- methylpyridin-2-amine
Figure imgf000373_0001
According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.1b (50 mg, 80 μmol, 1.0 eq). Aftzer work-up the residue obtained was purified by prep-HPLC 2 (gradient:1%-25% over 10 min). After prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give Example 19 as a yellow solid. Then the residue was further purified with SCX (see general protocol). 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.57 (d, J = 2.2 Hz, 1H), 8.04 (dd, J = 2.3, 8.8 Hz, 1H), 7.93 (d, J = 13.8 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 6.69 (s, 1H), 6.61 (d, J = 8.9 Hz, 1H), 3.99 (s, 3H), 3.84 - 3.70 (m, 2H), 3.67 - 3.53 (m, 2H), 2.94 (s, 3H), 2.92 - 2.62 (m, 4H), 2.05 - 1.95 (m, 1H), 1.91 - 1.81 (m, 1H), 1.78 - 1.56 (m, 4H). MS m/z (ESI) [M+H]+= 422.2. Example 20: 2-(6-(piperazin-1-yl)pyridin-3-yl)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinoline
Figure imgf000373_0002
According to Scheme 6 Step 2: Conditions 2 TFA with substrate E.1z (0.41 g, 0.68 mmol, 1.0 eq) in DCM (6.0 mL) and TFA (1.0 mL, 13 mmol, 19 eq). The mixture was stirred for 12 h at room temperature. After work-up the residue obtained was purified by prep-HPLC 5 to give Example 20 (0.17 g, 0.42 mmol, 62%) as a yellow powder. MS m/z (ESI) [M+H]+= 401.2 Attorney Docket No.: 185992002240 Example 21: (1-(2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) pyrrolidin-3-yl) methanol
Figure imgf000374_0001
According to Scheme 3 Step 3: Conditions 1 HCl with substrate C.2n (0.10 g, 0.20 mmol, 1.0 eq). After work-up the residue was first purified by prep-HPLC 8 (gradient:10%- 40% over 9 min) and then purified with SCX (see general protocol) to give Example 21 (0.35 g, 89 μmol, 43% yield, 100% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO- d6) δ (ppm): 8.92 (d, J = 2.4 Hz, 1H), 8.32 (dd, J = 9.0, 2.4 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 7.82 (dd, J = 8.4, 1.1 Hz, 1H), 7.58 (td, J = 7.6, 1.0 Hz, 1H), 7.31 (td, J = 7.7, 1.2 Hz, 1H), 6.94 (s, 1H), 6.89 (d, J = 9.0 Hz, 1H), 4.77 (s, 1H), 3.68 - 3.82 (m, 3H), 3.59 (dd, J = 9.8, 7.3 Hz, 1H), 3.49 - 3.53 (m, 4H), 3.21 - 3.32 (m, 2H), 2.71 - 2.91 (m, 4H), 2.39 - 2.48 (m, 1H), 2.02 - 2.14 (m, 1H), 1.78 - 2.00 (m, 1H). MS m/z (ESI) [M+H]+= 390.2. Example 22: 2-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-7-methyl-2,7- diazaspiro [4.5] decane
Figure imgf000374_0002
According to Scheme 3 Step 3: Conditions 1 HCl with substrate C.2q (0.10 g, 0.17 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 1%-31% over 10 min). The eluent was lyophilized to give Example 22 (19 mg, 41 μmol, 23% yield, 99% purity) as a yellow solid. Then the product was further purified with SCX (see general protocol). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.98 - 8.88 (m, 1H), 8.39 - 8.30 (m, 1H), 8.20 - 8.08 (m, 1H), 7.25 - 7.18 (m, 1H), 7.00 - 6.89 (m, 2H), 6.85 - 6.80 (m, 1H), 3.92 - 3.86 (m, 3H), 3.83 - 3.77 (m, 1H), 3.72 - 3.65 (m, 2H), 3.63 - 3.58 (m, 4H), 3.53 (br d, J = 9.8 Hz, 2H), 3.00 - 2.88 (m, 4H), 2.45 - 2.26 (m, 2H), 2.24 - 2.03 (m, 5H), 2.00 - 1.89 (m, 1H), 1.83 - 1.73 (m, 1H), 1.63 - 1.55 (m, 2H), 1.54 - 1.45 (m, 1H), 1.45 - 1.34 (m, 1H). MS m/z (ESI) [M+H]+= 473.3. Attorney Docket No.: 185992002240 Example 23: 7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(2,6-diazaspiro [3.4] octan-6- yl) quinoline
Figure imgf000375_0001
According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.1v (0.40 g, 0.63 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 0%-20% over 9 min). The eluent was lyophilized to give Example 23 (62 mg, 0.14 mmol, 23% yield, 100% purity) as a yellow solid. Then the product was further purified / neutralized with SCX (see general protocol). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.96 - 8.89 (m, 1H), 8.38 - 8.27 (m, 1H), 8.17 - 8.06 (m, 1H), 7.28 - 7.20 (m, 1H), 7.01 - 6.89 (m, 2H), 6.87 - 6.81 (m, 1H), 3.99 - 3.91 (m, 4H), 3.89 (s, 3H), 3.87 - 3.83 (m, 2H), 3.73 - 3.69 (m, 2H), 3.56 (br s, 4H), 2.92 - 2.82 (m, 4H), 2.59 (br d, J = 3.0 Hz, 2H), 2.32 - 2.22 (m, 2H). MS m/z (ESI) [M+H]+= 431.2. Example 24: 2-(7-methoxy-2-(4-(piperazin-1-yl) phenyl) quinolin-4-yl)-2,7-diazaspiro [4.5] decane
Figure imgf000375_0002
According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.1c (0.20 g, 0.30 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 2%-32% over 10 min). After prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give 2-[7-methoxy-2-(4- piperazin-1-ylphenyl) -4-quinolyl]-2, 9-diazaspiro [4.5] decane as a yellow solid. Then the product was further purified with SCX (see general protocol) to give Example 24 (17 mg, 37 μmol, 12% yield, 100% purity), which was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15 (d, J = 9.4 Hz, 1H), 8.06 (br d, J = 8.8 Hz, 2H), 7.22 (d, J = 2.8 Hz, 1H), 7.01 (br d, J = 8.9 Hz, 2H), 6.94 (dd, J = 2.6, 9.3 Hz, 1H), 6.84 (s, 1H), 3.89 (s, 3H), Attorney Docket No.: 185992002240 3.84 - 3.77 (m, 1H), 3.73 - 3.67 (m, 2H), 3.53 (br d, J = 10.3 Hz, 2H), 3.19 - 3.15 (m, 4H), 2.92 - 2.85 (m, 4H), 2.81 - 2.65 (m, 4H), 2.04 - 1.94 (m, 1H), 1.81 - 1.64 (m, 2H), 1.54 (br s, 2H). MS m/z (ESI) [M+H]+= 458.3. Example 25: (cis)-2-(4-(7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2- yl) phenoxy)-N-methylethan-1-amine
Figure imgf000376_0001
According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.1d (50 mg, 79 μmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 3 (gradient: 0%-30% B over 10 min). After prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give 2-[4-[4-(1, 3, 3a, 4, 5, 6, 7, 7a-octahydropyrrolo[3, 4-c]pyridin-2-yl) -7-methoxy-2-quinolyl]phenoxy]-N- methyl-ethanamine as a yellow solid. Then the product was further purified with SCX (see general protocol) to give Example 25 (11 mg, 26 μmol, 33% yield, 99% purity), which was obtained as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.23 (d, J = 9.4 Hz, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 8.5 Hz, 2H), 6.99 (dd, J = 1.7, 9.3 Hz, 1H), 6.72 (s, 1H), 4.17 (t, J = 5.0 Hz, 2H), 3.93 (s, 3H), 3.90 - 3.82 (m, 2H), 3.75 - 3.64 (m, 2H), 3.04 - 2.92 (m, 4H), 2.91 - 2.82 (m, 1H), 2.75 - 2.64 (m, 1H), 2.49 (s, 3H), 2.48 - 2.40 (m, 2H), 1.73 (br d, J = 9.0 Hz, 1H), 1.62 - 1.48 (m, 1H). MS m/z (ESI) [M+H]+= 433.3. Example 26: (cis)-6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl)-2-(6- (piperazin-1-yl) pyridin-3-yl) quinoline
Figure imgf000376_0002
According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.6e (0.12 mg, 0.17 μmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 3%-33% over 9 min) to give 4-(1,3,3a,4,5,6,7,7a-octahydropyrrolo[3,4-c] pyridin-2-yl)-6- Attorney Docket No.: 185992002240 fluoro-7-methoxy-2-(6-piperazin-1-yl-3-pyridyl) quinoline (HCl salt). Then this salt was basified with SCX (see general protocol) to give to give Example 26 (36 mg, 76 μmol, 44% yield, 99% purity), which was obtained as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.86 (d, J = 2.0 Hz, 1H), 8.27 (dd, J = 2.1, 8.9 Hz, 1H), 7.97 (d, J = 14 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 6.88 (d, J = 9.1 Hz, 1H), 6.82 (s, 1H), 3.95 (s, 3H), 3.87 - 3.80 (m, 1H), 3.76 (dd, J = 5.6, 8.9 Hz, 1H), 3.64 (s, 2H), 3.54 - 3.49 (m, 4H), 3.00 - 2.90 (m, 2H), 2.86 (d, J = 3.0 Hz, 1H), 2.79 (s, 4H), 2.73 - 2.64 (m, 1H), 2.41 (s, 2H), 1.68 (d, J = 9.8 Hz, 1H), 1.50 (dd, J = 1.5, 7.9 Hz, 1H). MS m/z (ESI) [M+H]+= 463.2. Example 27: 6-fluoro-N, N-dimethyl-2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-7-amine
Figure imgf000377_0001
According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.6f (0.15 g, 0.17 mmol, 1.0 eq). After work-up the residue was first purified by prep-HPLC 8 (gradient: 0%- 30% over 9 min) and then basified with SCX (see general protocol) to give Example 27 (23 mg, 46 μmol, 26% yield, 98% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.90 (d, J = 1.8 Hz, 1 H), 8.29 (dd, J = 8.9, 2.1 Hz, 1H), 7.86 (d, J = 16 Hz, 1H), 7.16 (d, J = 9.5 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 6.81 (s, 1H), 3.75 - 3.84 (m, 1H), 3.62 - 3.73 (m, 2H), 3.47 - 3.53 (m, 5H), 2.86 - 3.00 (m, 7H), 2.76 - 2.84 (m, 4H), 2.58 - 2.75 (m, 4H), 1.87 - 2.03 (m, 1H), 1.70 - 1.81 (m, 1H), 1.59 - 1.69 (m, 1H), 1.40 - 1.58 (m, 3H). MS m/z (ESI) [M+H]+= 490.3. Example 28: (cis)-2-(4-(6-fluoro-7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2-yl) phenoxy)-N-methylethan-1-amine
Figure imgf000377_0002
Attorney Docket No.: 185992002240 According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.1g (0.17 mg, 0.25 mmol, 1.0 eq). The reaction was diluted with water (0.50 mL) and purified by prep-HPLC 8 (gradient: 0%-30% over 9 min), followed by lyophilization. The product (HCl salt) was basified by SCX (see general protocol). Example 28 (41 mg, 91 μmol, 36% yield, 100% purity) was obtained as white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.13 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 14 Hz, 1H), 7.42 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 8.9 Hz, 2H), 6.89 (s, 1H), 4.09 (t, J = 5.6 Hz, 2H), 3.99 (s, 3H), 3.91 (br dd, J = 7.5, 8.7 Hz, 1H), 3.83 (br dd, J = 5.9, 9.8 Hz, 1H), 3.67 - 3.61 (m, 1H), 3.57 (br dd, J = 3.1, 9.6 Hz, 1H), 2.94 - 2.81 (m, 5H), 2.61 - 2.57 (m, 1H), 2.37 (s, 3H), 2.36 - 2.30 (m, 2H), 1.67 - 1.54 (m, 1H), 1.49 - 1.37 (m, 1H). MS m/z (ESI) [M+H]+= 451.4. Example 29: -5-(7-methoxy-4-(octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2- yl)-N, N-dimethylpyridin-2-amine
Figure imgf000378_0001
According to Scheme 5 Step 2: Conditions 1 HCl with substrate D.1a (0.30 g, 0.60 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 0%-30% over 9 min) to give 5-[4-(1,3,3a,4,5,6,7,7a-octahydropyrrolo[3,4-c] pyridin-2-yl)-7- methoxy-2-quinolyl]-N, N-dimethyl-pyridin-2-amine (HCl salt). Then 5-[4-(1,3,3a,4,5,6,7,7a- octahydropyrrolo[3,4-c] pyridin-2-yl)-7-methoxy-2-quinolyl]-N, N-dimethyl-pyridin-2-amine (HCl salt) was basified with SCX (see general protocol) to give Example 29 (24 mg, 60 μmol, 10% yield, 100% purity), which was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (d, J = 2.1 Hz, 1H), 8.30 (dd, J = 2.4, 8.9 Hz, 1H), 8.17 (d, J = 9.4 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 6.92 (dd, J = 2.6, 9.4 Hz, 1H), 6.81 (s, 1H), 6.72 (d, J = 9.0 Hz, 1H), 3.93 - 3.89 (m, 1H), 3.88 (s, 3H), 3.81 (dd, J = 5.9, 9.8 Hz, 1H), 3.64 - 3.59 (m, 1H), 3.55 (dd, J = 3.2, 9.6 Hz, 1H), 3.10 (s, 6H), 2.88 - 2.76 (m, 3H), 2.55 (d, J = 9.3 Hz, 1H), 2.33 (d, J = 4.6 Hz, 2H), 1.63 - 1.51 (m, 1H), 1.45 - 1.33 (m, 1H). MS m/z (ESI) [M+H]+= 404.2. Attorney Docket No.: 185992002240 Example 30: (1-(2-(6-(2-(cyclopropylamino) ethoxy) pyridin-3-yl)-6-fluoro-7- methoxyquinolin-4-yl) pyrrolidin-3-yl) methanol
Figure imgf000379_0001
According to Scheme 3 Step 3: Conditions 1 HCl with substrate C.2c (50 mg, 0.06 mmol, 65% purity, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 2%-30% over 9 min) to give Example 30 (10 mg, 0.02 mmol, 34% yield, 98% purity, HCl) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.77 ( s, 1H), 8.28 ( d, J = 13 Hz, 1H), 8.11 (d, J = 9.3 Hz, 1H), 7.76 (d, J = 7.96 Hz, 1H), 6.84 (s, 1H), 6.77 (d, J = 9.6 Hz, 1H), 4.52 ( t, J = 5.6 Hz, 2H), 4.23 - 4.02 (m, 6H), 3.96 - 3.85 (m, 1H), 3.77 - 3.65 (m, 4H), 2.93 - 2.84 (m, 1H), 2.72 - 2.60 (m, 1H), 2.33 - 2.23 (m, 1H), 2.05 – 1.93 (m, 1H), 1.05 – 0.97 (m, 2H), 0.97 - 0.91 (m, 2H). MS m/z (ESI) [M+H]+= 453.3. Example 31: 2-amino-1-(5-(6-fluoro-4-(3-(hydroxymethyl) pyrrolidin-1-yl)-7- methoxyquinolin-2-yl) pyridin-2-yl) propan-1-one
Figure imgf000379_0002
According to Scheme 3 Step 3: Conditions 1 HCl with substrate C.2d (0.16 g, 0.31 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 5%-35% over 9 min). The eluent was lyophilized to give Example 31 (21 mg, 48 μmol, 16% yield, 96% purity) as a yellow gum. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 14.69 - 14.43 (m, 1H), 9.52 - 9.44 (m, 1H), 8.85 - 8.77 (m, 1H), 8.65 - 8.51 (m, 3H), 8.38 - 8.28 (m, 2H), 8.23 - 8.13 (m, 1H), 7.17 - 6.98 (m, 1H), 5.30 - 5.18 (m, 1H), 4.22 - 4.06 (m, 3H), 4.05 - 4.02 (m, 3H), 3.94 - 3.82 (m, 1H), 3.55 - 3.50 (m, 2H), 2.68 - 2.59 (m, 1H), 2.20 - 2.08 (m, 1H), 1.93 - 1.81 (m, 1H), 1.61 - 1.52 (m, 3H). MS m/z (ESI) [M+H]+= 425.2. Attorney Docket No.: 185992002240 Example 32: 2-(2-(6-(azetidin-1-yl) pyridin-3-yl)-6-fluoro-7-methoxyquinolin-4-yl)-2,7- diazaspiro [4.5] decane
Figure imgf000380_0001
According to Scheme 5 Step 2: Conditions 2 TFA with substrate D.1b (0.10 g, 0.18 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 4%-24% over 10 min). After prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give 2-[2-[6-(azetidin-1- yl) -3-pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-2, 9-diazaspiro [4.5] decane as a white solid. The crude product was purified by prep-TLC with DCM/MeOH = 10:1 to give 2-[2-[6- (azetidin-1-yl) -3-pyridyl]-6-fluoro-7-methoxy-4-quinolyl]-2, 9-diazaspiro [4.5] decane as yellow oil. Then the product was neutralized with SCX (see general protocol) to give Example 32 (12 mg, 27 μmol, 15% yield, 98% purity), which was obtained as a white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.62 (d, J = 2.1 Hz, 1H), 8.14 (dd, J = 2.4, 8.8 Hz, 1H), 7.98 (d, J = 13.8 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 6.75 (s, 1H), 6.48 (d, J = 8.8 Hz, 1H), 4.13 (t, J = 7.4 Hz, 4H), 4.01 (s, 3H), 3.88 - 3.75 (m, 2H), 3.73 - 3.66 (m, 1H), 3.64 - 3.58 (m, 1H), 2.91 - 2.75 (m, 4H), 2.46 (quin, J = 7.5 Hz, 2H), 2.10 - 1.98 (m, 1H), 1.96 - 1.84 (m, 1H), 1.80 - 1.72 (m, 1H), 1.71 - 1.58 (m, 3H). MS m/z (ESI) [M+H]+= 488.3. Example 33: 2-amino-1-(4-(5-(7-methoxy-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl) propan-1-one
Figure imgf000380_0002
According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.1h (0.23 g, 0.32 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 2%-30% over 9 min) to give 2-amino-1-[4-[5-[4-(2,9-diazaspiro [4.5]decan-2-yl)-7-methoxy- 2-quinolyl]-2-pyridyl]piperazin-1-yl]propan-1-one (HCl salt). Then this salt was basified Attorney Docket No.: 185992002240 with SCX (see general protocol) to give Example 33 (16 mg, 28 μmol, 8.9% yield, 96% purity). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.96 (d, J = 1.8 Hz, 1H), 8.36 (dd, J = 2.2, 8.9 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 6.95 d, J = 9.0 Hz, 2H), 6.85 (s, 1H), 3.90 - 3.82 (m, 5H), 3.70 - 3.59 (m, 9H), 3.52 (d, J = 10.0 Hz, 2H), 2.71 - 2.57 (m, 4H), 1.99 - 1.92 (m, 1H), 1.79 - 1.73 (m, 1H), 1.65 - 1.48 (m, 4H), 1.12 (d, J = 6.7 Hz, 3H). MS m/z (ESI) [M+H]+= 530.4. Example 34: 4-(cis)-hexahydropyrrolo[3,4-c] pyrrol-2(1H)-yl)-2-(6-(piperazin-1-yl) pyridin- 3-yl) quinoline
Figure imgf000381_0001
According to Scheme 6 Step 2: Conditions 2 TFA with substrate E.1l (0.62 g, 1.0 mmol, 1.0 eq). The reaction mixture was evaporated and purified by prep-HPLC 6 and then prep-HPLC 7. After lyophilization, Example 34 was obtained (21 mg, 0.05 mmol, 5%) as a light-yellow powder. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.80 (s, 1H), 8.47 (d, J = 11 Hz, 1H), 8.22 (d, J = 8.9 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.86 (t, J = 8.7 Hz, 1H), 7.61 (t, J = 8.8 Hz, 1H), 7.10 (d, J = 6.4 Hz, 1H), 6.96 (s, 1H), 4.25 – 4.16 (m, 2H), 4.07 (m, 2H), 3.99 (s, 4H), 3.65 (m, 2H), 3.47 – 3.29 (m, 11H). MS m/z (ESI) [M+H]+= 401.20. Example 35: (cis)-1-(4-(5-(4-((1S,5S)-3,6-diazabicyclo [3.2.0] heptan-3-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl)-2-aminopropan-1-one
Figure imgf000381_0002
According to Scheme 6 Step 2: Conditions 2 TFA with substrate E.1m (0.52 g, 0.85 mmol, 1.0 eq). The reaction mixture was evaporated and purified by prep-HPLC 6. After lyophilization, Example 35 was obtained (0.32 g, 0.83 mmol, 97%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.89 (d, J = 2.6 Hz, 1H), 8.60 (d, J = 8.2 Hz, 1H), 8.30 (dd, J = 9.0, 2.7 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.99 (t, J = 7.7 Hz, 1H), 7.74 (t, J = Attorney Docket No.: 185992002240 7.8 Hz, 1H), 7.32 (s, 1H), 7.18 (d, J = 9.1 Hz, 1H), 5.29 – 5.21 (m, 1H), 4.72 (d, J = 12.3 Hz, 1H), 4.37 (dd, J = 11.4, 8.3 Hz, 1H), 4.17 (dd, J = 14.0, 5.7 Hz, 1H), 4.10 – 4.03 (m, 4H), 3.96 (dd, J = 11.4, 5.2 Hz, 2zH), 3.71 (p, J = 7.6 Hz, 1H), 3.40 (t, J = 5.3 Hz, 4H). 3.38 (s, 6H). MS m/z (ESI) [M+H]+= 387.20. Example 36: 2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(1,6-diazaspiro [3.4] octan-6-yl) quinoline
Figure imgf000382_0001
According to Scheme 6 Step 2: Conditions 2 TFA with substrate E.1n (0.41 mg, 0.69 mmol, 1.0 eq). The reaction mixture was evaporated and purified by prep-HPLC 6. After lyophilization, Example 36 was obtained (0.16 g, 0.39 mmol, 57%) as a yellow powder. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.77 (d, J = 2.6 Hz, 1H), 8.47 (d, J = 8.6 Hz, 1H), 8.18 (dd, J = 9.1, 2.7 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.89 (t, J = 7.8 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 9.1 Hz, 1H), 6.89 (s, 1H), 4.80 (m, 2H), 4.44 (d, J = 13.0 Hz, 1H), 4.25 – 4.16 (m, 2H), 4.09 – 4.02 (m, 2H), 4.02 – 3.96 (m, 4H), 3.37 – 3.27 (m, 4H), 2.97 – 2.74 (m, 3H), 2.53 (m, 1H). MS m/z (ESI) [M+H]+= 401.20. Example 37: 2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(2,7-diazaspiro [4.4] nonan-2-yl) quinoline
Figure imgf000382_0002
According to Scheme 6 Step 2: Conditions 2 TFA with substrate E.1o (0.28 g, 0.45 mmol, 1.0 eq). The reaction mixture was evaporated and purified by prep-HPLC 6. After lyophilization, Example 37 (80 mg, 0.19 mmol, 43%) was obtained as a yellow powder. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.81 (d, J = 2.6 Hz, 1H), 8.56 (d, J = 8.1 Hz, 1H), 8.22 (dd, J = 9.0, 2.6 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.66 (t, J = 8.5 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H), 6.91 (s, 1H), 4.27 – 4.13 (m, 4H), 4.07 – 4.00 (m, 4H), 3.56 – 3.40 (m, 4H), 3.40 – 3.34 (m, 4H), 2.39 – 2.14 (m, 4H). MS m/z (ESI) [M+H]+= 415.20. Attorney Docket No.: 185992002240 Example 38: 4-((trans)-hexahydropyrrolo[3,4-c] pyrrol-2(1H)-yl)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline
Figure imgf000383_0001
According to Scheme 6 Step 2: Conditions 2 TFA with substrate E.1p (0.18 g, 0.30 mmol, 1.0 eq). The reaction mixture was evaporated and purified by prep-HPLC 6. After lyophilization, Example 38 (36 mg, 0.09 mmol, 30%) was obtained as a yellow powder. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.81 (s, 1H), 8.51 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 6.4 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.93 (t, J = 7.7 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H), 6.94 (s, 1H), 4.23 (s, 2H), 4.13 – 4.00 (m, 6H), 3.70 (m, 2H), 3.41 – 3.34 (m, 4H), 3.27 (t, J = 11.3 Hz, 2H), 2.78 (m, 2H). MS m/z (ESI) [M+H]+= 401.20. Example 39: 4-((1S,5R)-3,6-diazabicyclo [3.2.0] heptan-6-yl)-2-(6-(piperazin-1-yl) pyridin- 3-yl) quinoline
Figure imgf000383_0002
According to Scheme 6 Step 2: Substrate E.1q (0.16 mg, 0.27 mmol, 1.0 eq) was dissolved into DCM (2.7 mL). and 2,2-difluoropropanoic acid (1.0 mL, 12 mmol, 44 eq) was added. The reaction was stirred for 12 h at rt. The reaction mixture was evaporated and purified twice by prep-HPLC 6. Example 39 (33 mg, 0.09 mmol, 31%) was obtained after lyophilization. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.78 (d, J = 2.6 Hz, 1H), 8.20 (dd, J = 9.0, 2.6 Hz,1H), 8.12 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.84 (t, J = 8.3 Hz, 1H), 7.58 (t, J = 7.1 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 6.71 (s, 1H), 5.68 – 5.61 (m, 1H), 4.83 (m, 1H), 4.64 (dd, J = 10.1, 4.3 Hz, 1H), 4.01 – 3.96 (m, 4H), 3.93 (m, 1H), 3.74 (d, J = 12.5 Hz, 1H), 3.68 – 3.59 (m, 1H), 3.37 (m, 1H), 3.35 – 3.30 (m, 5H). MS m/z (ESI) [M+H]+= 387.20. Attorney Docket No.: 185992002240 Example 40: 4-((1R,5R)-3,6-diazabicyclo [3.2.0] heptan-3-yl)-2-(6-(piperazin-1-yl) pyridin- 3-yl) quinoline
Figure imgf000384_0001
According to Scheme 6 Step 2: Conditions 2 TFA with substrate E.1r (0.11 g, 0.19 mmol, 1.0 eq). After work-up the crude was purified by prep-HPLC 6. After lyophilization, Example 40 (46 mg, 0.12 mmol, 62%) was obtained as a yellow powder. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.84 (d, J = 2.1 Hz, 1H), 8.55 (d, J = 8.8 Hz, 1H), 8.25 (dd, J = 9.0, 2.6 Hz, 1H), 8.05 (m, 1H), 7.94 (t, J = 8.4 Hz, 1H), 7.73 – 7.64 (m, 1H), 7.27 (s, 1H), 7.12 (d, J = 8.5 Hz, 1H), 5.23 – 5.15 (m, 1H), 4.66 (d, J = 12.2 Hz, 1H), 4.31 (dd, J = 11.3, 8.5 Hz, 1H), 4.10 (dd, J = 13.8, 5.9 Hz, 1H), 4.01 (t, J = 5.4 Hz, 4H), 3.90 (dd, J = 11.5, 5.2 Hz, 2H), 3.66 (m, 1H), 3.35 (m, 4H), 3.32 (s, 1H). MS m/z (ESI) [M+H]+= 387.20. Example 41: 4-((cis)-3,6-diazabicyclo [3.2.0] heptan-6-yl)-2-(6-(piperazin-1-yl) pyridin-3- yl) quinoline
Figure imgf000384_0002
According to Scheme 6 Step 2: Conditions 2 TFA with substrate E.1s (0.16 g, 0.27 mmol, 1.0 eq). After work-up the crude was purified by prep-HPLC 6 twice. After lyophilization, Example 41 (42 mg, 0.11 mmol, 41%) was obtained as a yellow powder. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.74 (m, 1H), 8.15 (m, 2H), 7.95 – 7.82 (m, 1H), 7.68 – 7.56 (m, 1H), 7.06 (m, 1H), 6.66 (s, 1H), 5.69 (m, 1H), 4.98 (m, 2H), 4.79 – 4.67 (m, 2H), 4.07 – 3.93 (m, 5H), 3.74 – 3.53 (m, 2H), 3.35 – 3.27 (m, 5H), 2.55 (m, 1H), 2.25 – 2.10 (m, 1H). MS m/z (ESI) [M+H]+= 387.20. Attorney Docket No.: 185992002240 Example 42: 2-(6-fluoro-7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-2,7- diazaspiro [4.5] decane
Figure imgf000385_0001
According to Scheme 1 Step 5: Conditions 2 SNAr: Substrate A.5d (0.10 g, 0.28 mmol, 1.0 eq) in pyrrolidine (2.0 mL) was stirred at 100 °C for 16 h. After cooling at room temperature and work-up the residue obtained was purified by prep-HPLC 7 (gradient: 39%- 69% over 10 min) to give Example 42 (46 mg, 0.12 mmol, 46% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.84 (d, J = 2.4 Hz, 1H), 8.27 (dd, J = 2.4, 8.6 Hz, 1H), 7.47 (s, 1H), 7.22 (s, 1H), 6.88 (s, 1H), 6.43 (d, J = 8.8 Hz, 1H), 4.01 (t, J = 7.6 Hz, 4H), 3.89 (d, J = 12 Hz, 6H), 3.71 - 3.66 (m, 4H), 2.39 - 2.32 (m, 2H), 1.99 (t, J = 6.0 Hz, 4H). MS m/z (ESI) [M+H]+= 391.1. Example 43: 2-amino-1-(4-(4-(7-methoxy-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-2-yl) phenyl) piperazin-1-yl) propan-1-one
Figure imgf000385_0002
According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.1j (80 mg, 0.11 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 3%-30% over 9 min) to give 2-amino-1-[4-[4-[4-(2,9-diazaspiro [4.5]decan-2-yl)-7-methoxy- 2-quinolyl]phenyl]piperazin-1-yl]propan-1-one (HCl salt). Then the salt was basified with SCX (see general protocol) to give Example 43 (25 mg, 48 μmol, 43% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.16 (d, J = 9.5 Hz, 1H), 8.08 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 2.7 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.94 (dd, J = 2.6, 9.4 Hz, 1H), 6.85 (s, 1H), 3.90 - 3.85 (m, 4H), 3.82 - 3.76 (m, 1H), 3.72 - 3.62 (m, 6H), 3.51 (d, J = 9.4 Hz, 1H), 3.28 - 3.23 (m, 4H), 2.73 - 2.57 (m, 4H), 2.01 - 1.91 (m, 1H), 1.81 - 1.71 (m, 1H), 1.67 - 1.60 (m, 1H), 1.57 - 1.46 (m, 3H), 1.13 (d, J = 6.7 Hz, 3H). MS m/z (ESI) [M+H]+= 529.5. Attorney Docket No.: 185992002240 Example 44: 4-(1,4-diazepan-1-yl)-6-fluoro-7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline
Figure imgf000386_0001
According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.1k (0.26 g, 0.41 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient:1%-23% over 10 min). After prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give Example 44 (37 mg, 85 μmol, 21% yield, 100% purity) as a white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 2.14 (br t, J = 4.9 Hz, 2H) 2.93 - 3.05 (m, 4H) 3.15 - 3.20 (m, 2H) 3.21 - 3.27 (m, 2H) 3.57 - 3.70 (m, 8H) 4.04 (s, 3H) 6.94 (d, J = 8.9 Hz, 1H) 7.24 (s, 1H) 7.49 (d, J = 8.3 Hz, 1H) 7.72 (d, J = 13 Hz, 1H) 8.22 (dd, J = 9.0, 2.4 Hz, 1H) 8.78 (d, J = 2.2 Hz, 1H). MS m/z (ESI) [M+H]+= 437.3. Example 45: 2-amino-1-(4-(4-(7-methoxy-4-(3-methoxypyrrolidin-1-yl) quinolin-2-yl) phenyl) piperazin-1-yl) propan-1-one
Figure imgf000386_0002
According to Scheme 3 Step 3: Conditions 1 HCl with substrate C.2i (0.50 g, 1.2 mmol, 1.0 eq). After work-up the residue obtained was solubilized in DMF (5.0 mL) and 2- (tert-butoxycarbonylamino) propanoic acid (0.27 g, 1.4 mmol, 1.2 eq), HATU (0.88 g, 2.3 mmol, 1.9 eq) and DIEA (0.45 g, 3.4 mmol, 0.60 mL, 2.9 eq) were added. The reaction mixture was stirred at 25 °C for 1 h. The residue was partitioned between ethyl acetate (20 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate (20 mL) twice. The combined organic layers were dried over (Na2SO4) and evaporated to give a crude material. The residue obtained was purified by Flash chromatography (12 g column, Eluent of 90~100% DCM/MeOH gradient at 40 mL/min) to afford tert-butyl N-[2-[4-[4-[7-methoxy- 4-(3-methoxypyrrolidin-1-yl) -2-quinolyl]phenyl]piperazin-1-yl]-1-methyl-2-oxo- Attorney Docket No.: 185992002240 ethyl]carbamate (0.28 g, 0.47 mmol, 40% yield, 80% purity) as yellow oil. MS m/z (ESI) [M+H] += 590.3. The same Conditions 1 HCl was used with the previous compound (0.28 g, 0.47 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 15%-45% over 10 min). After Prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give Example 45 (20 mg, 41 μmol, 8.7% yield, 100% purity) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.14 - 8.08 (m, 3H), 7.24 (d, J = 2.8 Hz, 1H), 7.06 (d, J = 8.9 Hz, 2H), 6.95 (dd, J = 2.8, 9.4 Hz, 1H), 6.87 (s, 1H), 4.12 (br s, 1H), 3.98 - 3.91 (m, 2H), 3.90 (s, 3H), 3.89 - 3.78 (m, 2H), 3.72 - 3.58 (m, 7H), 3.29 (s, 5H), 2.16 - 2.06 (m, 2H), 1.15 (d, J = 6.7 Hz, 3H). MS m/z (ESI) [M+H]+= 490.3. Example 46: 2-amino-1-(4-(5-(7-(dimethylamino)-4-(3-methoxypyrrolidin-1-yl) quinolin-2- yl) pyridin-2-yl) piperazin-1-yl) propan-1-one
Figure imgf000387_0001
According to Scheme 3 Step 3: Conditions 1 HCl with substrate C.2k (0.17 g, 0.36 mmol, 1.0 eq). After work-up the residue obtained was solubilized in DMF (2.0 mL) and 2- (tert-butoxycarbonylamino) propanoic acid (0.14 mg, 0.73 mmol, 2.0 eq), HATU (0.41 g, 1.1 mmol, 3.0 eq) and N-ethyl-N-propan-2-ylpropan-2-amine (0.23 g, 1.8 mmol, 0.32 μL, 5.0 eq) were added. After stirring at 25 °C for 16 h, the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by prep-HPLC 2 (gradient: 22%-52% over 10 min) to give tert-butyl N-[2-[4-[5-[7-(dimethylamino)-4-(3-methoxypyrrolidin-1-yl)- 2-quinolyl]-2-pyridyl]piperazin-1-yl]-1-methyl-2-oxo-ethyl]carbamate (0.2 g, 0.30 mmol, 82% yield, 90% purity) as a yellow solid. MS m/z (ESI) [M+H]+= 604.8. The same Conditions 1 HCl was used with the previous compound (0.10 g, 0.17 mmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 10%-40% over 9 min), to give 2-amino-1-[4-[5-[7-(dimethylamino)-4-(3-methoxypyrrolidin- 1-yl)-2-quinolyl]-2-pyridyl] piperazin-1-yl] propan-1-one (HCl salt). Then the salt was basified with SCX (see general protocol) to give Example 46 (23 mg, 46 μmol, 28% yield, 100% purity) as a yellow gum. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.09 (s, 1H), 8.88 Attorney Docket No.: 185992002240 (d, J = 2.3 Hz, 1H), 8.19 - 8.45 (m, 5H), 7.35 (d, J = 2.58 Hz, 1H), 6.98 - 7.19 (m, 2H), 6.66 (s, 1H), 3.43 - 4.22 (m, 14H), 3.30 (s, 3H), 3.11 (s, 6H), 2.02 - 2.29 (m, 2H), 1.36 (d, J = 7.0 Hz, 3H). MS m/z (ESI) [M+H]+= 504.2. Example 47: ethyl (2-(6-(methylamino) pyridin-3-yl)-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-7-yl) carbamate
Figure imgf000388_0001
To a solution of E.1w (0.15 g, 0.27 mmol, 1.0 eq) in dioxane (3.0 mL) was added ethyl carbamate (35 mg, 0.39 mmol, 1.5 eq), BrettPhos Pd G3 (25 mg, 28 μmol, 0.10 eq) and t-BuONa (80 mg, 0.83 mmol, 3.1 eq), The mixture was degassed and purged with nitrogen three times, then the resulting mixture was stirred at 60 °C for 12 h. The residue was partitioned between ethyl acetate (10 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) twice. The combined organic layers were dried over (Na2SO4) and evaporated to give a crude material. Compound tert-butyl 2-[7- (ethoxycarbonylamino) -2-[6-(methylamino) -3-pyridyl]-4-quinolyl]-2, 7-diazaspiro [4.5] decane-7-carboxylate (100 mg, crude) was obtained as yellow oil. MS m/z (ESI) [M+H]+= 561.4 According to Scheme 3 Step 3: Conditions 1 HCl with tert-butyl 2-[7- (ethoxycarbonylamino) -2-[6-(methylamino) -3-pyridyl]-4-quinolyl]-2, 7-diazaspiro [4.5] decane-7-carboxylate (20 mg, 36 μmol, 1.0 eq). After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 2%-32% over 10 min). After prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give Example 47 (4.6 mg, 9.9 μmol, 28% yield, 100% purity) as yellow oil. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.57 (d, J = 2.3 Hz, 1H), 8.51 (s, 2H), 8.44 - 8.35 (m, 2H), 7.97 (dd, J = 2.4, 8.9 Hz, 1H), 7.46 (dd, J = 2.2, 9.4 Hz, 1H), 6.73 - 6.65 (m, 2H), 4.27 (q, J = 7.1 Hz, 2H), 4.13 (br t, J = 6.6 Hz, 2H), 4.08 - 3.93 (m, 2H), 3.26 - 3.19 (m, 2H), 3.19 - 3.10 (m, 2H), 2.97 (s, 3H), 2.26 - 2.07 (m, 2H), 1.95 - 1.77 (m, 4H), 1.35 (t, J = 7.1 Hz, 3H). MS m/z (ESI) [M+H]+= 461.3. Attorney Docket No.: 185992002240 Example 48: 2-amino-N-(4-(6-fluoro-7-methoxy-4-((cis)-octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2-yl) phenyl)-3-methylbutanamide
Figure imgf000389_0001
According to Scheme 6 Step 2: Conditions 1 HCl with substrate E.1x (0.20 g, 0.29 mmol, 1,0 eq) stirred with HCl/dioxane (2 mL) for 1 h. After work-up the residue was purified by prep-HPLC 2 (gradient:1%-25% over 4 min). The eluent was lyophilized directly to give the title compound as formate. Then the formate was neutralized with SCX (see general protocol) to give Example 48 (20 mg, 41 μmol, 14% yield, 100% purity) as white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.14 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 14 Hz, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 9.0 Hz, 1H), 6.91 (s, 1H), 3.98 (s, 3H), 3.91 (t, J = 8.3 Hz, 1H), 3.82 (dd, J = 6.2, 9.4 Hz, 1H), 3.63 (t, J = 8.3 Hz, 1H), 3.59-3.53 (m, 1H), 3.14 (d, J = 5.5 Hz, 2H), 2.92 - 2.78 (m, 3H), 2.62 - 2.54 (m, 2H), 2.41 - 2.31 (m, 2H), 2.03 - 1.90 (m, 1H), 1.66-1.55 (m, 1H), 1.49 - 1.35 (m, 1H), 1.00 - 0.82 (m, 6H). MS m/z (ESI) [M+H]+= 492.3. Example 49: 2-amino-1-(4-(5-(6-fluoro-7-methoxy-4-((cis)-octahydro-2H-pyrrolo[3,4-c] pyridin-2-yl) quinolin-2-yl) pyridin-2-yl) piperazin-1-yl)-2-methylpropan-1-one
Figure imgf000389_0002
According to Scheme 6 Step 2: Conditions 1 HCl: Substrate E.1y (0.19 g, 0.25 mmol, 1.0 eq) was added to HCl/dioxane (2 M, 2.0 mL, 16 eq) and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated to give a residue. The residue obtained was purified by prep-HPLC 7 (gradient: 0%-30% over 9 min). After Prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give Example 49 (22 mg, 39 μmol, 16% yield, 100% purity) as a Attorney Docket No.: 185992002240 white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 1.56 (s, 6 H) 1.62 - 1.75 (m, 1 H) 1.80 - 1.90 (m, 1 H) 2.57 (br s, 2 H) 2.80 - 2.91 (m, 1 H) 2.96 - 3.04 (m, 1 H) 3.06 - 3.14 (m, 2 H) 3.68 - 3.82 (m, 6 H) 3.91 (br s, 6 H) 4.03 (s, 3 H) 6.80 (s, 1 H) 6.97 (d, J = 8.9 Hz, 1 H) 7.44 (d, J = 8.7 Hz, 1 H) 8.02 (d, J = 14 Hz, 1 H) 8.20 (dd, J = 8.9, 2.5 Hz, 1 H) 8.77 (d, J = 2.2 Hz, 1 H). MS m/z (ESI) [M+H]+= 548.4. Example 50: 5-[4-(2, 9-diazaspiro[4.5]decan-2-yl) -7-methoxy-2-quinolyl]-N, N-dimethyl- pyridin-2-amine
Figure imgf000390_0001
According to Scheme 5 Step 2: Conditions 1 HCl: On substrate D.1e (0.10 g, 0.19 mmol, 1.0 eq) in dioxane (2.0 mL) was added HCl/dioxane (2 M) and the reaction mixture was stirred at 25 °C for 2 h. After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 0%-30% over 10 min). Then the solid was neutralized with SCX (see general protocol to give Example 50 (20 mg, 46 μmol, 24% yield, 95% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (d, J = 2.2 Hz, 1H), 8.31 (dd, J = 2.4, 8.8 Hz, 1H), 8.16 (d, J = 9.4 Hz, 1H), 7.20 (d, J = 2.6 Hz, 1H), 6.93 (dd, J = 2.8, 9.4 Hz, 1H), 6.84 (s, 1H), 6.72 (d, J = 9.0 Hz, 1H), 3.88 (s, 3H), 3.84 - 3.76 (m, 1H), 3.74 - 3.63 (m, 2H), 3.52 (d, J = 10.0 Hz, 1H), 3.10 (s, 6H), 2.71 - 2.55 (m, 4H), 2.02 - 1.91 (m, 1H), 1.81 - 1.70 (m, 1H), 1.69 - 1.59 (m, 1H), 1.58 - 1.43 (m, 3H). MS m/z (ESI) [M+H]+= 418.3. Example 51: 2-(4-(piperazin-1-yl) phenyl)-4-(pyrrolidin-1-yl) quinoline
Figure imgf000390_0002
According to Scheme 3 Step 3: Conditions 1 HCl: On substrate C.2r (0.30 g, 0.65 mmol, 1.0 eq) in dioxane (5.0 mL) was added HCl/dioxane (4.0 M, 2.0 mL, 12 eq). The mixture was stirred 2 h at 25 °C. After work-up the residue was poured into ACN (10 mL) and was added K2CO3 (35 mg, 0.25 mmol, 1.0 eq). The mixture was stirred at 25 °C for 16 h. The mixture was adjusted to pH = 7~8 with NH3.H2O. The mixture was concentrated to give Attorney Docket No.: 185992002240 a residue. After work-up, purification was done by prep-HPLC 9 (gradient: 0-10 minutes 8~38%) to give Example 51(17 mg, 47 mmol, 19% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.23 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.30 (t, J = 6.8 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.96 (s, 1H), 3.71 (t, J = 6.0 Hz, 4H), 3.17 - 3.10 (m, 4H), 2.88 - 2.82 (m, 4H), 2.03 - 1.95 (m, 4H). MS m/z (ESI) [M+H]+= 359.3. Example 52: (1-(2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) pyrrolidin-3-yl) methanol
Figure imgf000391_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of C.2n (0.10 g, 0.20 mmol, 1.0 eq) in dioxane (1.0 mL) was added HCl/dioxane (2 M, 2.0 mL, 20 eq). After stirring at 25 °C for 4 h, the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by prep-HPLC 8 (gradient: 10%-40% over 9 min) to and neutralized with SCX (see general protocol) to give Example 52 (35 mg, 89 μmol, 43% yield, 100% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.92 (d, J = 2.4 Hz, 1H), 8.32 (dd, J = 9.0, 2.4 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 7.82 (dd, J = 8.4, 1.1 Hz, 1H), 7.58 (td, J = 7.6, 1.0 Hz, 1H), 7.31 (td, J = 7.7, 1.2 Hz, 1H), 6.94 (s, 1H), 6.89 (d, J = 9.0 Hz, 1H), 4.77 (s, 1H), 3.68 - 3.82 (m, 3H), 3.59 (dd, J = 9.8, 7.3 Hz, 1H), 3.49 - 3.53 (m, 4H), 3.21 - 3.32 (m, 2H), 2.71 - 2.91 (m, 4H), 2.39 - 2.48 (m, 1H), 2.02 - 2.14 (m, 1H), 1.78-2.001 (m, 1H). MS m/z (ESI) [M+H]+= 390.2. Example 53: (1-(6-amino-7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) pyrrolidin-3-yl) methanol
Figure imgf000391_0002
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of C.2s (0.20 g, 0.29 mmol, 1.0 eq) in MeOH (5.0 mL) was added TFA (0.33 g, 2.9 mmol, 10 eq) at 25 °C. The Attorney Docket No.: 185992002240 mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue, The residue obtained was purified by prep-HPLC 8 (gradient: 0%- 30% over 10 min) to give N-(4-(3-(hydroxymethyl)pyrrolidin-1-yl)-7-methoxy-2-(6- (piperazin-1-yl)pyridin-3-yl)quinolin-6-yl)acetamide HCl salt and Example 53 HCl salt as a yellow solid. The HCl salt products were neutralized by SCX (see general protocol) to give N-[4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2-(6-piperazin-1-yl-3-pyridyl)-6- quinolyl]acetamide (25 mg, 0.05 μmol, 18% yield, 98% purity) as a yellow solid and Example 53 (35 mg, 0.08 mmol, 28% yield, 100% purity) as a yellow solid. Acetamide product: MS m/z (ESI) [M+H] + = 477.3. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.84 (d, J = 2.0 Hz, 1H), 8.24 (dd, J = 8.8, 2.0 Hz, 1H), 7.33 (s, 1H) ,7.14 (s, 1H), 6.80 - 6.89 (m, 2H), 5.06 (s, 2H), 4.80-4.65 (m, 1H), 3.92 (s, 3H), 3.64 - 3.59 (m, 2H), 3.53 - 3.41 (m, 8H), 2.81 (s, 4H), 2.47 - 2.40 (m, 1H), 2.05 (dd, J = 12, 5.6 Hz, 1H), 1.80 - 1.68 (m, 1H). MS m/z (ESI) [M+H]+= 435.3. Example 54: 2-amino-1-(5-(6-fluoro-7-methoxy-4-(2,7-diazaspiro[4.5]decan-2-yl)quinolin- 2-yl)pyridin-2-yl)propan-1-one
Figure imgf000392_0001
According to Scheme 6 Step 2: Conditions 1 HCl: On substrate E.1aa (35 mg, 53 μmol, 1.0 eq)was added HCl/dioxane (2 M, 26 μL, 1.0 eq). The mixture was stirred 2 h at 25 °C. After work-up the residue obtained was purified by prep-HPLC 8 (gradient: 1%-30% over 10 min). The eluent was lyophilized to give Example 54 (5.4 mg, 12 μmol, 22% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 9.40 - 9.34 (m, 1H), 8.71 - 8.62 (m, 1H), 8.43 - 8.35 (m, 2H), 7.66 - 7.62 (m, 1H), 7.09 (br d, J = 2.0 Hz, 1H), 5.44 (s, 1H), 4.35 - 4.17 (m, 4H), 4.14 - 4.06 (m, 5H), 3.24 - 3.20 (m, 2H), 2.28 - 2.19 (m, 2H), 1.97 - 1.87 (m, 4H), 1.73 - 1.67 (m, 3H). MS m/z (ESI) [M+H]+= 464.3. Attorney Docket No.: 185992002240 Example 55: [4-[5-[4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2-quinolyl]-2-pyridyl] piperazin-1-yl]-pyrrolidin-2-yl-methanone
Figure imgf000393_0001
According to Scheme 3 Step 3: Conditions 1 HCl: On substrate C.2t (0.12 g, 0.19 mmol, 1.0 eq) was added HCl/dioxane (2 M, 1.0 mL) and the mixture was stirred at 25 °C for 4 h. After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 4%-34% over 10 min) and product was neutralized by SCX (see general protocol) to give Example 55 (24 mg, 43 μmol, 22% yield, 96% purity) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.94 (d, J = 2.3 Hz, 1H), 8.35 (dd, J = 2.3, 8.9 Hz, 1H), 8.15 (d, J = 9.4 Hz, 1H), 7.22 (d, J = 2.8 Hz, 1H), 6.95 (td, J = 2.7, 9.2 Hz, 2H), 6.84 (s, 1H), 4.79 - 4.66 (m, 1H), 3.96 (dd, J = 6.1, 7.7 Hz, 1H), 3.89 (s, 3H), 3.78 - 3.71 (m, 3H), 3.66 - 3.57 (m, 8H), 3.52 - 3.44 (m, 4H), 3.06 - 2.99 (m, 1H), 2.71 (td, J = 6.8, 10.7 Hz, 1H), 2.46 - 2.40 (m, 1H), 2.11 - 2.01 (m, 2H), 1.82 - 1.60 (m, 4H). MS m/z (ESI) [M+H]+= 517.3. Example 56: 2-(6-(piperazin-1-yl) pyridin-3-yl)-4-(2,7-diazaspiro [4.4] nonan-2-yl) quinoline
Figure imgf000393_0002
According to Scheme 6 Step 2: Conditions 2 TFA.: On substrate E.1ab (0.28 g, 0.45 mmol, 1.0 eq) was added TFA (29 eq) and the mixture was stirred 12 h at 25 °C. After work- up the residue obtained was purified by prep-HPLC 5 to give Example 56 (80 mg, 0.19 mmol, 43%) as a yellow powder. MS m/z (ESI) [M+H]+= 415.2. Attorney Docket No.: 185992002240 Example 57: 6-(2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-2-oxa-6-azaspiro [3.4] octane
Figure imgf000394_0001
According to Scheme 3 Step 3: Conditions 2 TFA: To a substrate C.2u (0.11 g, 0.21 mmol, 1.0 eq) was added TFA (62 eq) and the mixture was stirred12 h at 25 °C. After work- up the residue obtained was purified by prep-HPLC 5 to give Example 57 (48 mg, 0.12 mmol, 57%) as a yellow powder. MS m/z (ESI) [M+H]+= 401.2. Example 58: 2-((5-(7-methoxy-4-(2,7-diazaspiro [4.5] decan-2-yl) quinolin-2-yl) pyridin-2- yl) oxy)-N-methylethan-1-amine
Figure imgf000394_0002
According to Scheme 6 Step 2: Conditions 1 HCl: To a substrate E.1ac (0.10 g, 0.15 mmol, 1.0 eq) in EtOAc (0.5 mL) was added HCl/EtOAc (4.0 M, 2.0 mL, 52 eq) and the mixture was stirred 1 h at 25 °C. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by prep-HPLC 2 (gradient: 2-8 min 10-34%) and product was then neutralized by SCX (see general protocol) to give Example 58 (18 mg, 39 μmol, 25% yield, 97% purity) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.51-8.50 (m, 1H), 8.31- .30 (m, 1H), 8.18- 8.16 (m, 1H), 7.20- 7.19 (m, 1H), 6.97 – 6.96 (m, 1H), 6.76 (s, 1H), 6.49 – 6.46 (m, 1H), 4.09- 4.07 (m, 2H), 3.88 (s, 3H), 3.78 - 3.75 (m, 1H), 3.64- 3.62 (m, 2H), 3.55 - 3.52 (m, 1H), 2.83 – 2.81 (m, 2H), 2.66-2.63 (m, 4H), 2.31 (s, 3H), 1.79-1.77 (m, 1H), 1.62- 1.59 (m, 1H), 1.56- 1.53 (m, 4H). MS m/z (ESI) [M+H]+= 448.2. Attorney Docket No.: 185992002240 Example 59: 2-amino-1-(4-(5-(6-fluoro-7-methoxy-4-((cis)-octahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)pyridin-2-yl)piperazin-1-yl)propan-1-one
Figure imgf000395_0001
According to Scheme 6 Step 2: Conditions 1 HCl: Substrate E.1ad (0.20 g, 0.27 mmol, 1.0 eq) was added to HCl/dioxane (2.0 M, 2.0 mL, 15 eq) and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated to give a residue. The residue obtained was purified by prep-HPLC 8 (gradient: 0%-29% over 10 min). After prep- HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give Example 59 (24 mg, 46 μmol, 17% yield, 100% purity) as a white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 1.31 (d, J = 6.9 Hz, 3H), 1.55 - 1.69 (m, 1H), 1.72 - 1.86 (m, 1H), 2.53 (br d, J = 3.1 Hz, 2H), 2.74 - 2.83 (m, 1H), 2.92 - 2.99 (m, 1H), 3.01 - 3.08 (m, 2H), 3.64 - 3.73 (m, 4H), 3.74 - 3.82 (m, 6H), 3.86 - 3.94 (m, 2H), 4.01 (s, 1H), 4.03 (s, 3H), 6.79 (s, 1H), 6.98 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 14 Hz, 1H) 8.20 (dd, J = 8.9, 2.5 Hz, 1H), 8.77 (d, J = 2.2 Hz, 1H). MS m/z (ESI) [M+H]+= 534.2. Example 60: 2-amino-1-[5-[4-(2,9-diazaspiro [4.5]decan-2-yl)-7-(dimethylamino)-6-fluoro- 2-quinolyl]-2-pyridyl]propan-1-one
Figure imgf000395_0002
According to Scheme 6 Step 2: Conditions 1 HCl: To a substrate E.1ae (50 mg, 74 μmol, 1.0 eq) in dioxane (1.0 mL) was added HCl/dioxane (2.0 M, 4.0 mL) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by prep-HPLC 5 (gradient: 1%-31% over 9 min) to give Example 60 (15 mg, 30 μmol, 40% yield, 100% purity, HCl) as an orange gum. 1H NMR Attorney Docket No.: 185992002240 (400 MHz, DMSO-d6) δ (ppm): 9.18 - 9.60 (m, 3H) 8.82 (dd, J = 8.2, 2.2 Hz, 1H) 8.52 (s, 3H) 8.27 (d, J = 8.3 Hz, 1H) 8.19 (d, J = 17 Hz, 1H) 7.77 (d, J = 9.0 Hz, 1 ) 6.93 (s, 1H) 5.11 - 5.38 (m, 1H) 4.33 (dd, J = 12, 3.2 Hz, 1H) 4.09 - 4.24 (m, 2H) 3.97 (d, J = 12 Hz, 1 H) 3.14 (d, J = 1.8 Hz, 6H) 2.95 - 3.13 (m, 4H) 2.19 - 2.31 (m, 1H) 1.96 - 2.09 (m, 1H) 1.65 - 1.91 (m, 4H) 1.60 (d, J = 7.1 Hz, 3H). MS m/z (ESI) [M+H]+= 477.2. Example 61: 2-((5-(6-fluoro-4-((cis)-octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)pyridin-2-yl)oxy)-N-methylethan-1-amine
Figure imgf000396_0001
According to Scheme 6 Step 2: Conditions 1 HCl: A substrate E.1af (0.19 g, 0.25 mmol, 1.0 eq) was added into HCl/dioxane (4.0 mL), and then the resulting mixture was stirred at 25 °C for 1 h. The crude material was purified by prep-HPLC 2 (gradient: 1%-10% over 10 min). The eluent was lyophilized directly to give the title compound as formate. Then the formate was neutralized with SCX (see general protocol) to give Example 61 (30 mg, 71 μmol, 29% yield, 100% purity) as white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.51 (d, J = 2.3 Hz, 1H), 8.30 (dd, J = 2.4, 9.5 Hz, 1H), 7.99 (dd, J = 2.5, 12 Hz, 1H), 7.85 (dd, J = 6.1, 9.2 Hz, 1H), 7.56 - 7.45 (m, 1H), 6.86 (s, 1H), 6.49 (d, J = 9.5 Hz, 1H), 4.08 (t, J = 6.2 Hz, 2H), 3.94 (t, J = 8.6 Hz, 1H), 3.87-3.79 (m, 1H), 3.67 - 3.61 (m, 1H), 3.58-3.54 (m, 1H), 2.91 - 2.75 (m, 5H), 2.59 - 2.53 (m, 1H), 2.41 - 2.31 (m, 2H), 2.30 (s, 3H), 1.64 - 1.54 (m, 1H), 1.47 - 1.35 (m, 1H). MS m/z (ESI) [M+H]+= 422.2. Example 62: 2-((5-(6,7-difluoro-4-((cis)-octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin- 2-yl)pyridin-2-yl)oxy)-N-methylethan-1-amine
Figure imgf000396_0002
According to Scheme 6 Step 2: To a substrate E.1ag (100 mg, 156.32 μmol, 1 eq) in dioxane (2 mL) was added HCl/dioxane (2 M, 2 mL) at 25 °C. The mixture was stirred at 25 Attorney Docket No.: 185992002240 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by prep-HPLC 2 (gradient: 1%-10% over 10 min). Then the solid was neutralized with SCX (see general protocol) to give Example 62 (20 mg, 46 μmol, 29% yield, 100% purity) as yellow gum. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.52 (d, J = 2.4 Hz, 1H), 8.34 - 8.16 (m, 2H), 7.71 (dd, J = 8.4, 12.2 Hz, 1H), 6.86 (s, 1H), 6.49 (d, J = 9.6 Hz, 1H), 4.07 (t, J = 6.2 Hz, 2H), 3.98 - 3.88 (m, 1H), 3.83 (dd, J = 6.2, 9.6 Hz, 1H), 3.69 - 3.61 (m, 1H), 3.60 - 3.53 (m, 1H), 2.91 - 2.74 (m, 5H), 2.61 - 2.53 (m, 1H), 2.42 - 2.33 (m, 3H), 2.30 (s, 3H), 1.59 (dd, J = 2.6, 11.6 Hz, 1H), 1.48 - 1.32 (m, 1H). MS m/z (ESI) [M+H]+= 440.2. Example 63: N-[4-[4-(2, 9-diazaspiro[4.5]decan-2-yl) -6-fluoro-7-methoxy-2- quinolyl]phenyl]acetamide
Figure imgf000397_0001
According to Scheme 5 Step 2: To a substrate D.1c (0.10 g, 0.18 mmol, 1.0 eq) in DCM (1.0 mL) was added 2, 6-dimethylpyridine (0.37 g, 3.4 mmol, 0.40 mL, 19 eq). Then TMSOTf (0.25 g, 1.1 mmol, 0.20 mL, 6.1 eq) was added into the mixture at 0 °C. The resulting solution was stirred at 25 °C for 1 h. The reaction mixture was concentrated to give a residue. The filter liquor was purified by prep-HPLC 2 (gradient: 4%-34% over 10 min), and the product was then neutralized with SCX (see general protocol) to give Example 63 (11 mg, 25 μmol, 14% yield, 100% purity) off-white solid. 1H NMR (400 MHz, methanol-d4, 298 K) δ (ppm): 8.01 (d, J = 13.6 Hz, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.6 Hz, 1H), 6.84 (s, 1H), 4.02 (s, 3H), 3.90 - 3.80 (m, 2H), 3.75 - 3.70 (m, 1H), 3.67 - 3.61 (m, 1H), 2.95 - 2.83 (m, 4H), 2.17 (s, 3H), 2.05 (td, J = 6.6, 12.8 Hz, 1H), 1.98 - 1.91 (m, 1H), 1.80 - 1.66 (m, 4H). MS m/z (ESI) [M+H]+= 449.3. Attorney Docket No.: 185992002240 Example 64: 5-[7-chloro-4-(2, 9-diazaspiro[4.5]decan-2-yl) -2-quinolyl]-N-methyl-pyridin- 2-amine
Figure imgf000398_0001
According to Scheme 6 Step 2: Conditions 1 HCl: To a solution of E.1ah (0.10 g, 0.16 mmol, 1.0 eq) in dioxane (3.0 mL) was added HCl/dioxane (1.0 M, 2.0 mL) at 25 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by prep-HPLC 8 (gradient: 5%-35% over 10 min). Then the solid was purified with SCX (see general protocol) to give Example 64 (25 mg, 58 μmol, 35% yield, 95% purity) as a yellow solid. 1H NMR (400 MHz, DMSO- d6) δ (ppm): 8.86 (s, 1H), 8.37 - 8.11 (m, 2H), 7.79 (d, J = 1.6 Hz, 1H), 7.29 (dd, J = 1.8, 9.2 Hz, 1H), 6.95 - 6.77 (m, 2H), 6.54 (d, J = 8.8 Hz, 1H), 3.91 - 3.77 (m, 1H), 3.77 - 3.64 (m, 2H), 3.54 (d, J = 10.0 Hz, 1H), 2.85 (d, J = 4.6 Hz, 3H), 2.75 - 2.53 (m, 4H), 2.03 - 1.90 (m, 1H), 1.82 - 1.71 (m, 1H), 1.67 - 1.43 (m, 4H). MS m/z (ESI) [M+H]+= 408.2. Example 65: 2-(6-piperazin-1-yl-3-pyridyl)-4-[(1R,5S)-3,6-diazabicyclo [3.2.0] heptan-6-yl] quinoline
Figure imgf000398_0002
According to Scheme 6 Step 2: Conditions 2 TFA: To a solution of E.1ai (75 mg, 0.13 mmol, 1.0 eq) TFA (101 eq) was added at at 25 °C. The mixture was stirred at 25 °C for 24 h. After work-up the residue obtained was purified by prep-HPLC 5 to give Example 65 (66 mg, 0.17 mmol, quant.) as a yellow powder. MS m/z (ESI) [M+H]+= 387.1. Attorney Docket No.: 185992002240 Example 66: 2-amino-1-(4-(5-(4-(3-(hydroxymethyl) pyrrolidin-1-yl)-7-methoxyquinolin-2- yl) pyridin-2-yl) piperazin-1-yl)-3-methylbutan-1-one
Figure imgf000399_0001
To a solution of Example 10 (0.15 g, 0.36 mmol, 1.0 eq) in DMF (2.0 mL) was added HATU (0.21 g, 0.54 mmol, 1.5 eq), 2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (90 mg, 0.41 mmol, 1.2 eq) and DIEA (0.14 g, 1.1 mmol, 0.19 mL, 3.0 eq) at 25 °C. The mixture was stirred at 25 °C for 16 h. After work-up tert-butyl N-[1-[4-[5-[4-[3- (hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2-quinolyl]-2-pyridyl] piperazine-1-carbonyl]- 2-methyl-propyl] carbamate (0.23 g, 0.28 mmol, 79% yield, 76% purity) was obtained as yellow gum. MS m/z (ESI) [M+H]+= 619.3 According to Scheme 3 Step 3: To a solution of tert-butyl N-[1-[4-[5-[4-[3- (hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2-quinolyl]-2-pyridyl] piperazine-1-carbonyl]- 2-methyl-propyl] carbamate (0.23 g, 0.37 mmol, 1.0 eq) in dioxane (1.0 mL) was added HCl/dioxane (2 M, 1.0 mL) at 25 °C. The mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by prep- HPLC 2 (gradient:4%-34% over 10 min) to give 2-amino-1-[4-[5-[4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2-quinolyl]-2-pyridyl] piperazin-1-yl]-3-methyl-butan-1-one (FA salt). Then the salt was basified with SCX (see general protocol) to give Example 66 (22 mg, 39 μmol, 11% yield, 94% purity) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.94 (d, J = 2.3 Hz, 1H), 8.35 (dd, J = 2.3, 8.9 Hz, 1H), 8.15 (d, J = 9.4 Hz, 1H), 7.22 (d, J = 2.8 Hz, 1H), 6.97 - 6.92 (m, 2H), 6.84 (s, 1H), 4.74 (s, 1H), 3.89 (s, 3H), 3.78 - 3.46 (m, 17H), 2.46 - 2.40 (m, 1H), 2.11 - 2.03 (m, 1H), 1.82 - 1.71 (m, 2H), 0.91 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H). MS m/z (ESI) [M+H]+= 519.3. Attorney Docket No.: 185992002240 Example 67: 2-amino-1-[4-[5-[4-[3-(hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2- quinolyl]-2-pyridyl] piperazin-1-yl]-4-methyl-pentan-1-one
Figure imgf000400_0001
To a solution of Example 10 (0.15 g, 0.36 mmol, 1.0 eq) in DMF (2.0 mL) was added HATU (0.21 g, 0.54 mmol, 1.5 eq), 2-(tert-butoxycarbonylamino)-4-methyl-pentanoic acid (90 mg, 0.39 mmol, 1.1 eq) and DIEA (0.14 g, 1.1 mmol, 0.19 mL, 3.0 eq) at 25 °C. The mixture was stirred at 25 °C for 4 h. After work-up tert-butyl N-[1-[4-[5-[4-[3- (hydroxymethyl) pyrrolidin-1-yl]-7-methoxy-2-quinolyl]-2-pyridyl] piperazine-1-carbonyl]- 3-methyl-butyl] carbamate (0.20 g, 0.19 mmol, 52% yield, 59% purity) was obtained as yellow gum. MS m/z (ESI) [M+H]+= 633.4 According to Scheme 3 Step 3: To a solution of tert-butyl N-[1-[4-[5-[4-[3- (hydroxymethyl)pyrrolidin-1-yl]-7-methoxy-2-quinolyl]-2-pyridyl]piperazine-1-carbonyl]-3- methyl-butyl]carbamate (0.20 g, 0.19 mmol, 1.0 eq) in dioxane (0.50 mL) was added HCl/dioxane (2.0 M, 1.0 mL) at 25 °C. The mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by prep- HPLC 2 (gradient: 2%-32% over 10 min) and neutralized with SCX (see general protocol) to give Example 67 (27 mg, 50 μmol, 27% yield, 100% purity) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.94 (d, J = 2.1 Hz, 1H), 8.36 (dd, J = 2.3, 8.9 Hz, 1H), 8.15 (d, J = 9.4 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H), 6.95 (td, J = 2.5, 9.3 Hz, 2H), 6.84 (s, 1H), 4.95 - 4.54 (m, 1H), 3.89 (s, 3H), 3.84 - 3.44 (m, 17H), 2.47 - 2.39 (m, 1H), 2.06 (dq, J = 5.8, 11.4 Hz, 1H), 1.85 - 1.70 (m, 2H), 1.37 - 1.23 (m, 2H), 0.90 (dd, J = 6.8, 9.0 Hz, 6H). MS m/z (ESI) [M+H]+= 533.20 Attorney Docket No.: 185992002240 Example 68: 2-(azetidin-1-yl)-5-[4-(2,9-diazaspiro [4.5]decan-2-yl)-7-methoxy-2- quinolyl]thiazole
Figure imgf000401_0001
According to Scheme 5 Step 2: Conditions 2 TFA: To a substrate D.1d (0.15 g, 0.28 mmol, 1.0 eq) was added TFA (1.0 mL). The mixture was stirred 1 h at 25 °Cwas added 2, 6- dimethylpyridine (0.37 g, 3.4 mmol, 0.40 mL, 19 eq). TFA (1.0 mL), stirred at rt for 1 h. After work-up the residue obtained was purified by prep-HPLC 2 (gradient: 2%-32% over 10 min). After prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give Example 68 (25 mg, 58 μmol, 21% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 1.62 - 1.81 (m, 4H) 1.86 - 1.95 (m, 1H) 2.04 (dt, J = 13, 6.4 Hz, 1H) 2.56 (quin, J = 7.4 Hz, 2H) 2.76 - 2.92 (m, 4H) 3.54 - 3.72 (m, 2H) 3.75 - 3.87 (m, 2H) 3.93 (s, 3H) 4.19 (t, J = 7.4 Hz, 4H) 6.73 (s, 1H) 6.98 (br d, J = 9.3 Hz, 1H) 7.23 (d, J = 1.1 Hz, 1H) 7.81 (s, 1H) 8.17 (d, J = 9.7 Hz, 1H). MS m/z (ESI) [M+H]+= 436.3. Example 73: 2-(4-(6-fluoro-7-(methoxy-d3)-4-((cis)-octahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)phenoxy)-N-methylethan-1-amine
Figure imgf000401_0002
According to Scheme 6 Step 2: Conditions 1 HCl: To a substrate E.1aj (350 mg, 535.33 μmol, 1 eq) was added to HCl/dioxane (2 M, 5 mL, 18.68 eq). The reaction mixture was stirred at 25°C for 1hour. The reaction mixture was concentrated and the residue was purified by prep-HPLC 1 (gradient:0%-30% over 9 min). After Prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give Example 73 (60.36 mg, 131.75 μmol, 24.61% yield, 99% purity) as a white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 1.50 - 1.65 (m, 1 H) 1.69 - 1.80 (m, 1 Attorney Docket No.: 185992002240 H) 2.43 - 2.51 (m, 5 H) 2.71 (ddd, J=12.62, 8.89, 3.42 Hz, 1 H) 2.86 - 2.92 (m, 1 H) 2.95 - 3.02 (m, 4 H) 3.61 - 3.75 (m, 2 H) 3.81 - 3.93 (m, 2 H) 4.18 (t, J=5.26 Hz, 2 H) 6.79 (s, 1 H) 7.09 (d, J=8.80 Hz, 2 H) 7.43 (d, J=8.80 Hz, 1 H) 7.92 (d, J=8.68 Hz, 2 H) 8.00 (d, J=13.82 Hz, 1 H). MS m/z (ESI) [M+H]+= 454.3. Example 75: (1-(7-(dimethylamino)-2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4- yl)pyrrolidin-3-yl)methanol
Figure imgf000402_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of C.2v (60 mg, 112.64 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M) at 25°C. After stirring at 25 °C for 2 hours, the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient:10%-40% over 9 min) to give Example 75 (32.17 mg, 68.59 μmol, 60.89% yield, 100% purity, HCl) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.01 (s, 1 H) 9.61 (s, 2 H) 8.87 (d, J=2.50 Hz, 1 H) 8.33 (dd, J=9.08, 2.56 Hz, 1 H) 8.26 (d, J=9.76 Hz, 1 H) 7.32 (d, J=2.63 Hz, 1 H) 7.14 (d, J=9.14 Hz, 1 H) 7.05 (dd, J=9.68, 2.68 Hz, 1 H) 6.62 (d, J=1.14 Hz, 1 H) 3.86 - 4.09 (m, 7 H) 3.70 - 3.85 (m, 1 H) 3.43 - 3.58 (m, 2 H) 3.19 (s, 4 H) 3.10 (s, 6 H) 2.41 - 2.49 (m, 1 H) 2.05 - 2.16 (m, 1 H) 1.83-1.80 (m, 1 H). MS m/z (ESI)433.1 [M+H]+. [M+H]+= 436.3. Example 77: (1-(7-methoxy-2-(6-(2-(methylamino)ethoxy)pyridin-3-yl)quinolin-4- yl)pyrrolidin-3-yl)methanol
Figure imgf000402_0002
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of C.2w (270 mg, 531.89 μmol, 1 eq) in EtOAc (0.5 mL) was added HCl/EtOAc (2 M, 3 mL, 11.28 eq) at 20 °C. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC 1 (gradient: 2-9 min 11-41%). The salt was basified by strong cation exchange resin (CNWBOND SCX, SPE Cartridge). 1/ Wash resin with deionized water (10.0 mL). 2/ Wash resin with the salt in MeOH (2.0 mL) (target was adsorbed to the resin. 3/ Wash resin with Attorney Docket No.: 185992002240 deionized water (5.0 mL) until the pH of the solution is neutral. 4/ Wash resin with NH3.H2O/MeOH=1/20 (10.0 mL), target was cleaved from the resin. 5/ Concentration and lyophilization give Example 77 (22.25 mg, 51.38 μmol, 9.66% yield, 94.1% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.25-8.23 (m, 1H), 7.90-7.88 (m, 2H), 7.32-7.31 (m, 1H), 7.11-7.09 (m, 2H), 7.02-7.00 (m, 1H), 6.72 (s, 1H), 4.20-4.19 (m, 2H), 3.95 (s, 3H), 3.90 - 3.78 (m, 3H), 3.74 - 3.61 (m, 3H), 3.04-3.03 (m, 2H), 2.57 - 2.54 (m, 1H), 2.52 (s, 3H), 2.19-2.17 (m, 1H), 1.91 - 1.87 (m, 1H). MS m/z (ESI) [M+H]+= 408.2. Example 79: ethyl (2-(2-(azetidin-1-yl)thiazol-5-yl)-4-((cis)-octahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-7-yl)carbamate
Figure imgf000403_0001
According to Scheme 5 Step 2: Conditions 3 TMSOTf: To a solution of D.1f (50 mg, 86.40 μmol, 1 eq) in DCM (1 mL) was added TMSOTf (61.50 mg, 276.71 μmol, 50 μL, 3.20 eq) and 2,6-dimethylpyridine (92.00 mg, 858.59 μmol, 100 μL, 9.94 eq) at 0°C. After stirring at 0°C for 0.5 hours, the reaction mixture was concentrated under reduced pressure to give a residue at 25°C. The residue was purified by prep-HPLC 2 (gradient:5%-35% over 10 min) to give Example 79 (4.85 mg, 10.13 μmol, 11.73% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.94 (s, 1 H), 7.91 (d, J=14.14 Hz, 1 H), 7.23 (d, J=9.02 Hz, 1 H), 6.82 (s, 1 H), 4.75 (t, J=5.26 Hz, 1 H), 4.06 (t, J=7.50 Hz, 4 H), 3.95 (s, 3 H), 3.61 - 3.78 (m, 3 H), 3.44 - 3.59 (m, 3 H), 2.36 - 2.48 (m, 3 H), 2.05 (dq, J=11.94, 6.14 Hz, 1 H), 1.65 - 1.85 (m, 1 H). MS m/z (ESI) [M+H]+= 479.1. Example 83: 2-amino-1-(4-(7-(dimethylamino)-6-fluoro-4-((cis)-octahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)phenyl)propan-1-one
Figure imgf000403_0002
According to Scheme 6 Step 2: Conditions 1 HCl: To a solution of E.1aq (0.1 g, 151.10 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M, 4 mL) at 25°C. After Attorney Docket No.: 185992002240 stirring at 25°C for 1 hour, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC 1 (gradient:0%-30% over 9 min) to give Example 83 (62.72 mg, 135.88 μmol, 89.93% yield, 100% purity) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 14.06 (s, 1 H) 9.42 - 9.89 (m, 2 H) 8.71 (d, J=3.76 Hz, 3 H) 8.22 - 8.41 (m, 4 H) 8.16 (d, J=16.76 Hz, 1 H) 7.88 (d, J=9.02 Hz, 1 H) 6.83 (s, 1 H) 5.21 - 5.33 (m, 1 H) 3.64 - 4.76 (m, 4 H) 3.20 (s, 2 H) 3.09 (s, 6 H) 2.96 - 3.06 (m, 1 H) 2.79 (d, J=5.76 Hz, 1 H) 2.58 - 2.70 (m, 1 H) 1.96 (s, 1 H) 1.79 (br d, J=11.64 Hz, 1 H) 1.48 (d, J=7.14 Hz, 3 H). MS m/z (ESI) [M+H]+= 462-2. Example 84: 2-(4-(6-fluoro-4-((cis)-octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-7-(pent-4-yn- 1-yloxy)quinolin-2-yl)phenoxy)-N-methylethan-1-amine
Figure imgf000404_0001
According to Scheme 6 Step 2: Conditions 1 HCl: To a solution of E.1ar (120 mg, 170.73 μmol, 1 eq) in dioxane (2 mL) was added HCl/dioxane (4 M, 1 mL, 23.43 eq), then the resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by prep-HPLC 2 (gradient:0%-30% over 10 min]; gradient:36%-56% B over min) to give Example 84 (36.39 mg, 71.46 μmol, 41.85% yield, 98.7% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.32 (s, 2H), 8.06 - 7.97 (m, 3H), 7.44 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 6.80 (s, 1H), 4.30 - 4.21 (m, 5H), 3.84 - 3.70 (m, 4H), 3.33 (t, J = 4.6 Hz, 2H), 3.26 - 3.16 (m, 2H), 3.11 - 2.98 (m, 2H), 2.73 - 2.65 (m, 2H), 2.64 (s, 3H), 2.59 - 2.54 (m, 1H), 2.36 (dt, J = 2.4, 6.9 Hz, 2H), 2.03 - 1.95 (m, 2H), 1.91 (d, J = 8.1 Hz, 1H), 1.78 - 1.64 (m, 1H).MS m/z (ESI) [M+H]+= 503.2. Attorney Docket No.: 185992002240 Example 85: 2-(6-(azetidin-1-yl)pyridin-3-yl)-7-methoxy-4-((cis)-octahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinoline
Figure imgf000405_0001
According to Scheme 5 Step 2: Conditions 3 TMSOTf: To a solution of D.1g (100 mg, 193.93 μmol, 1 eq) in DCM (1 mL) was added 2, 6-dimethylpyridine (368.00 mg, 3.43 mmol, 0.4 mL, 17.71 eq) and TMSOTf (246.00 mg, 1.11 mmol, 0.2 mL, 5.71 eq). The reaction mixture was stirred at 0 °C for 0.5 hour. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC 2 (gradient:1%-25% over 10 min). The salt was basified by strong cation exchange resin (CNWBOND SCX, SPE Cartridge). 1/ Wash resin with deionized water 10.0 mL. 2/ Wash resin with the salt in MeOH (2.0 mL) (target was adsorbed to the resin. 3/ Wash resin with deionized water (10.0 mL) until the pH of the solution is neutral. 4/ Wash resin with NH3.H2O/MeOH=1/20 (21 mL), target was cleaved from the resin. 5/ Concentration and lyophilization give Example 85 (40.36 mg, 97.13 μmol, 50.08% yield, 100% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.87 (d, J = 2.3 Hz, 1H), 8.29 (dd, J = 2.3, 8.7 Hz, 1H), 8.18 (d, J = 9.4 Hz, 1H), 7.20 (d, J = 2.6 Hz, 1H), 6.92 (dd, J = 2.8, 9.4 Hz, 1H), 6.79 (s, 1H), 6.43 (d, J = 8.6 Hz, 1H), 4.01 (t, J = 7.4 Hz, 4H), 3.93 - 3.89 (m, 1H), 3.88 (s, 3H), 3.81 (br dd, J = 5.9, 9.4 Hz, 1H), 3.66 - 3.59 (m, 1H), 3.55 (br dd, J = 3.3, 9.5 Hz, 1H), 2.89 - 2.74 (m, 3H), 2.58 - 2.53 (m, 1H), 2.39 - 2.30 (m, 4H), 1.63 - 1.53 (m, 1H), 1.46 - 1.32 (m, 1H). MS m/z (ESI) [M+H]+= 416.2. Example 87: 2-(4-(6-fluoro-7-methoxy-4-(2,7-diazaspiro[4.5]decan-2-yl)quinolin-2- yl)phenoxy)-N-methylethan-1-amine
Figure imgf000405_0002
According to Scheme 6 Step 2: Conditions 1 HCl: E.1as (222 mg, 333.93 μmol, 1 eq) was added to HCl/dioxane (2 M, 5 mL, 29.95 eq), the reaction mixture was stirred at 25 °C for 2 hours. LCMS showed desired MS was detected. The reaction mixture was concentrated Attorney Docket No.: 185992002240 to give a residue. The residue was purified by prep-HPLC 1 (gradient:0%-30% over 9 min). After Prep-HPLC purification, the eluent was concentrated to remove organic solvents to give Example 87 (58.46 mg, 116.68 μmol, 34.94% yield, 100% purity, HCl) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.58 - 1.85 (m, 4 H) 1.89 - 2.03 (m, 1 H) 2.16 - 2.29 (m, 1 H) 2.63 (t, J=5.38 Hz, 3 H) 2.89 - 3.20 (m, 4 H) 3.31 - 3.42 (m, 2 H) 4.01 (s, 3 H) 4.05 - 4.20 (m, 2 H) 4.27 (br d, J=11.88 Hz, 1 H) 4.44 (br t, J=5.00 Hz, 2 H) 6.83 (s, 1 H) 7.24 (d, J=8.88 Hz, 2 H) 8.20 (d, J=8.88 Hz, 2 H) 8.26 - 8.37 (m, 2 H) 9.34 - 9.67 (m, 4 H) 13.97 (s, 1 H). MS m/z (ESI) [M+H]+= 465.3. Example 89: 2-amino-N-(5-(6-fluoro-7-methoxy-4-((cis)-octahydro-2H-pyrrolo[3,4- c]pyridin-2-yl)quinolin-2-yl)pyridin-2-yl)-2-methylpropanamide
Figure imgf000406_0001
According to Scheme 6 Step 2: Conditions 1 HCl: To a screw-cap vial equipped with a magnetic stir bar was added E.1at (30 mg, 44.2 μmol, 1 eq) and HCl/dioxane (2 M, 1 mL) sequentially. The vial was sealed with a teflon-lined septum. Then the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC 1 (gradient:0%-27% over 9 min), followed by lyophilization to Example 89 (13 mg, 27.1 μmol, 61.4% yield, 99.9% purity, 3 HCl salt) as yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.99 (d, J = 1.8 Hz, 1H), 8.48 - 8.43 (m, 1H), 8.43 - 8.38 (m, 1H), 8.33 (d, J = 13.1 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 6.97 (s, 1H), 4.39 - 4.12 (m, 4H), 4.12 (s, 3H), 3.47 - 3.36 (m, 2H), 3.30 - 3.20 (m, 2H), 2.97 - 2.89 (m, 1H), 2.87 - 2.79 (m, 1H), 2.19 - 2.06 (m, 1H), 2.02 - 1.92 (m, 1H), 1.76 (s, 6H). MS (ESI) m/z=479.3 [M+H]+. [M+H]+= 479.3. Example 91: (1-(7-methoxy-2-(4-(piperazin-1-yl)phenyl)quinolin-4-yl)pyrrolidin-3- yl)methanol
Figure imgf000406_0002
Attorney Docket No.: 185992002240 According to Scheme 3 Step 3: Conditions 1 HCl: C.2x (280 mg, 539.87 μmol, 1 eq) was added to HCl/dioxane (5 mL), then the resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to give crude material which was purified by Prep- HPLC 2 (gradient:4%-34%over 10 min). The eluent was lyophilized directly to give Example 91 (218 mg, 467.91 μmol, 86.67% yield, 99.71% purity, Formate) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.24 (s, 1H), 8.19 (d, J = 9.4 Hz, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 2.6 Hz, 1H), 7.08 (d, J = 9.0 Hz, 2H), 6.98 (dd, J = 2.7, 9.3 Hz, 1H), 6.82 (s, 1H), 3.83 - 3.71 (m, 3H), 3.62-3.57 (m, 1H), 3.56 - 3.46 (m, 2H), 3.46 - 3.36 (m, 4H), 3.22-3.09 (m, 4H), 2.48 - 2.39 (m, 1H), 2.12-2.02 (m, 1H), 1.83-1.72 (m, 1H). MS m/z (ESI) [M+H]+= 419.2. Example 97: (1-(6-fluoro-7-methoxy-2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4- yl)pyrrolidin-3-yl)methanol
Figure imgf000407_0001
According to Scheme 3 Step 3: Conditions 1 HCl: A solution of C.2y (250 mg, 465.01 μmol, 1 eq) in HCl/dioxane (5 mL) was stirred at 25°C for 1 hour. The crude material was concentrated to give a crude material which was purified by Prep-HPLC 1 (gradient:6%- 36% B over 9 min). The eluent was lyophilized directly to give the title compound as HCl salt. Then the HCl salt was basified with SCX cation exchange resin to Example 97 (66 mg, 150.10 μmol, 32.28% yield, 99.5% purity) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (d, J = 2.0 Hz, 1H), 8.30 (dd, J = 2.3, 9.0 Hz, 1H), 7.95 (d, J = 14.2 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 6.92 - 6.82 (m, 2H), 4.74 (br t, J = 5.1 Hz, 1H), 3.98 (s, 3H), 3.77 - 3.65 (m, 3H), 3.60 - 3.43 (m, 7H), 2.85 - 2.75 (m, 4H), 2.46 - 2.39 (m, 1H), 2.11 - 2.01 (m, 1H), 1.83 - 1.71 (m, 1H). MS m/z (ESI) [M+H]+= 438.2. Example 98: [1-[7-(dimethylamino)-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4- quinolyl]pyrrolidin-3-yl]methanol
Figure imgf000407_0002
Attorney Docket No.: 185992002240 According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of C.2z (130 mg, 249.21 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M, 2 mL) and at 25°C .The mixture was stirred at 25°C for 2 hours, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC 2 (gradient:2%-32% over 10 min) to give Example 98 (82.43 mg, 195.55 μmol, 78.47% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.90 (d, J=2.26 Hz, 1 H) 8.47 (dd, J=8.64, 2.50 Hz, 1 H) 8.26 (s, 2 H) 8.12 (d, J=9.52 Hz, 1 H) 6.89 - 7.02 (m, 3 H) 6.72 (s, 1 H) 4.54 (t, J=5.28 Hz, 2 H) 3.71 - 3.81 (m, 3 H) 3.43 - 3.61 (m, 3 H) 3.26 (t, J=5.28 Hz, 2 H) 3.04 (s, 6 H) 2.57 (s, 3 H) 2.37 - 2.48 (m, 1 H) 2.09 - 2.07 (m, 1 H) 1.79 - 1.77 (m, 1 H). MS m/z (ESI) [M+H]+= 422.2. Example 101: 2-[4-[4-(2,9-diazaspiro[4.5]decan-2-yl)-6-fluoro-7-(trideuteriomethoxy)-2- quinolyl]phenoxy]-N-methyl-ethanamine
Figure imgf000408_0001
According to Scheme 6 Step 2: Conditions 1 HCl: To a solution of E.1au (200 mg, 299.48 μmol, 1 eq) in dioxane (0.5 mL) was added HCl/dioxane (2 M, 2 mL, 13.36 eq) at 25°C. The mixture was stirred at 25°C for 2 hours, concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient:1%-30% B over 9 min) to give Example 101 (129.14 mg, 256.20 μmol, 85.55% yield, 100% purity, HCl) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.30 (d, J = 13.2 Hz, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 6.88 (s, 1H), 4.46 - 4.41 (m, 2H), 4.27 - 4.14 (m, 3H), 4.03 ( d, J = 11.2 Hz, 1H), 3.53 (t, J = 4.8 Hz, 2H), 3.36 - 3.31 (m, 3H), 3.27 - 3.16 (m, 2H), 2.83 (s, 3H), 2.30 - 2.12 (m, 2H), 2.00 - 1.79 (m, 4H). MS m/z (ESI) [M+H]+= 468.2. Example 110: (cis)-2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000408_0002
Attorney Docket No.: 185992002240 According to Scheme 6 Step 2: Conditions 1 HCl: To a solution of E.1av (200 mg, 365.86 μmol, 1 eq) in dioxane (0.5 mL) was added HCl/dioxane (2 M, 2 mL) at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient:5%-35% over 0 min). The salt was basified by strong cation exchange resin (CNWBOND SCX, SPE Cartridge). 1/ Wash resin with deionized water 20.0 mL. 2/ Wash resin with the salt in MeOH (4.0 mL) (target was adsorbed to the resin. 3/ Wash resin with deionized water (20.0 mL) until the pH of the solution is neutral. 4/ Wash resin with NH3.H2O/MeOH=1/10 (21 mL), target was cleaved from the resin. 5/ Concentration and lyophilization give Example 110 (62.55 mg, 135.31 μmol, 36.99% yield, 96.6% purity) as a off-white solid. 1H NMR (400 MHz, DMSO- d6) δ (ppm): 8.19 - 8.12 (m, 3H), 7.74 ( s, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.98 (dd, J = 2.8, 9.2 Hz, 1H), 6.93 (s, 1H), 4.16 (t, J = 5.4 Hz, 2H), 3.98 - 3.93 (m, 1H), 3.91 - 3.85 (m, 5H), 3.55 ( dd, J = 5.2, 10.2 Hz, 1H), 3.31 - 3.22 (m, 2H), 3.04 - 2.98 (m, 3H), 2.81 - 2.72 (m, 1H), 2.45 (s, 3H), 1.94 - 1.85 (m, 1H), 1.73 - 1.61 (m, 1H). MS m/z (ESI) [M+H]+= 447.3. Example 113: [1-[7-(dimethylamino)-2-[4-[2-(methylamino)ethoxy]phenyl]-4- quinolyl]pyrrolidin-3-yl]methanol
Figure imgf000409_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl N-[2-[4- [7-(dimethylamino)-4-[3-(hydroxymethyl)pyrrolidin-1-yl]-2-quinolyl]phenoxy]ethyl]-N- methyl-carbamate (300 mg, 576.19 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M, 10 mL) at 25°C. After stirring at 25°C for 1 hour, the reaction mixture was concentrated under reduced pressure and residue was purified by prep-HPLC 1 (gradient:8%-38% over 10 min) basified by SCX cation exchange resin to give Example 113 (41 mg, 97.49 μmol, 16.92% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.01 - 8.18 (m, 3 H) 6.94 - 7.10 (m, 3 H) 6.91 (d, J=2.57 Hz, 1 H) 6.71 (s, 1 H) 4.47 (s, 1 H) 4.25 (2, 1 H) 4.08 (t, J=5.56 Hz, 2 H) 3.67 - 3.76 (m, 3 H) 3.44 - 3.57 (m, 3 H) 3.02 (s, 6 H) 2.83 - 2.95 (m, 2 H) 2.41 - 2.48 (m, 1 H) 2.36 (s, 3 H) 2.06 (dq, J=11.56, 5.74 Hz, 1 H) 1.69 - 1.83 (m, 1 H). MS m/z (ESI)421.2 [M+H]+. [M+H]+= 421.2. Attorney Docket No.: 185992002240 Example 120: (cis)-N,N-dimethyl-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4- c]pyridin-2-yl)-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]quinolin-7-amine
Figure imgf000410_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of C.2aa (200 mg, 356.68 μmol, 1 eq) in dioxane (0.5 mL) was added HCl/dioxane (2 M, 1.86 mL) at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient:1%-31% over 10 min) to give product. The product was purified by prep-TLC (SiO2, DCM: MeOH= 8:1) to give Example 120 (33.03 mg, 71.71 μmol, 20.10% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.67 (d, J = 2.4 Hz, 1H), 8.24 - 8.14 (m, 2H), 7.05 - 7.00 (m, 2H), 6.94 (d, J = 8.6 Hz, 1H), 6.56 (s, 1H), 4.47 (t, J = 5.3 Hz, 2H), 3.87 - 3.79 (m, 3H), 3.71 (dd, J = 5.6, 9.8 Hz, 1H), 3.08 (s, 7H), 2.99 (t, J = 5.4 Hz, 2H), 2.56 ( s, 4H), 2.47 (s, 3H), 2.42 - 2.33 (m, 2H), 2.29 (s, 3H), 1.85 ( dd, J = 4.2, 7.8 Hz, 1H), 1.73- 1.65 (m, 1H). MS m/z (ESI) [M+H]+= 461.3. Example 125: N,N-dimethyl-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-(6-methyl-2,6- diazaspiro[3.3]heptan-2-yl)quinolin-7-amine
Figure imgf000410_0002
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of C.2ab (150 mg, 281.60 μmol, 1 eq) in DCM (2 mL) was added TFA (614.00 mg, 5.38 mmol, 0.4 mL) at 25 °C .The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC 3 (gradient:4%- 34% over 12 min) basified by SCX cation exchange resin to give Example 125 (63.62 mg, 147.08 μmol, 52.23% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.80 (d, J = 2.2 Hz, 1H), 8.37 (dd, J = 2.4, 8.6 Hz, 1H), 7.75 (d, J = 9.4 Hz, 1H), Attorney Docket No.: 185992002240 6.99 (dd, J = 2.4, 9.3 Hz, 1H), 6.92 - 6.87 (m, 2H), 6.41 (s, 1H), 4.39 - 4.32 (m, 6H), 3.32 (s, 4H), 2.99 (s, 6H), 2.85 (t, J = 5.5 Hz, 2H), 2.31 (s, 3H), 2.18 (s, 3H). MS m/z (ESI) [M+H]+= 433.4. Example 126: 2-[4-[7-methoxy-4-(2-oxa-7-azaspiro[3.4]octan-7-yl) -2-quinolyl]phenoxy]- N-methyl-ethanamine
Figure imgf000411_0001
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of C.2ac (240 mg, 461.87 μmol, 1 eq) in DCM (2.5 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 14.57 eq) at 20°C. The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (gradient: 3- 12 min 9-39% flow 25 mL/min) basified by SCX cation exchange resin to give Example 126 (91.97 mg, 204.26 μmol, 44.22% yield, 93.17% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15 - 8.13 (m, 3H), 7.26-7.25 (m, 1H), 7.05-7.03 (m, 2H), 6.98-6.97 (m, 1H), 6.88 (s, 1H), 4.65-4.64 (m, 2H), 4.56-4.55 (m, 2H), 4.09-4.08 (m, 2H), 3.96 (s, 2H), 3.90 (s, 3H), 3.72-3.71 (m, 2H), 2.87-2.86 (m, 2H), 2.37 (s, 3H), 2.29-2.27 (m, 2H). MS m/z (ESI) [M+H]+= 420.3. Example 131: [1-[2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-7-morpholino-4- quinolyl]pyrrolidin-3-yl]methanol
Figure imgf000411_0002
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of C.2ad (50 mg, 88.70 μmol, 1 eq) in MeOH (1 mL) was added HCl/MeOH (2 M, 1 mL) at 25°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was added K2CO3 to adjust at pH>7. Then the mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL, 3 times). The combined organic layers were washed with brine (35 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by prep-TLC Attorney Docket No.: 185992002240 (SiO2, Dichloromethane: Methanol=5:1) to give Example 131 (12.85 mg, 27.72 μmol, 31.25% yield, 100% purity). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (d, J = 2.2 Hz, 1H), 8.51 - 8.40 (m, 1H), 8.13 (d, J = 9.3 Hz, 1H), 7.16 (dd, J = 2.6, 9.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.80 (s, 1H), 4.81 - 4.69 (m, 1H), 4.38 (t, J = 5.7 Hz, 2H), 3.81 - 3.70 (m, 7H), 3.57 (dd, J = 7.2, 9.6 Hz, 1H), 3.53 - 3.45 (m, 2H), 3.28 - 3.24 (m, 4H), 2.90 (t, J = 5.7 Hz, 2H), 2.46 - 2.40 (m, 1H), 2.37 (s, 3H), 2.11 - 2.02 (m, 1H), 1.83 - 1.72 (m, 1H). MS m/z (ESI)464.3 [M+H]+. [M+H]+= 464.3. Example 132: N,N-dimethyl-2-[5-[2-(methylamino)ethoxy]-2-pyridyl]-4-(2-oxa-7- azaspiro[3.4]octan-7-yl)quinolin-7-amine
Figure imgf000412_0001
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of  tert-butyl N-[2- [[6-[7-(dimethylamino)-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)-2-quinolyl]-3- pyridyl]oxy]ethyl]-N-methyl-carbamate (450 mg, 843.23 μmol, 1 eq) in DCM (4 mL) was added TFA (6.14 g, 53.85 mmol, 4 mL, 63.86 eq) ,The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated and the residue was purified by prep- HPLC 2 (gradient:5%-35% over 10 min) basified by SCX cation exchange resin to give Example 132 (130 mg, 287.86 μmol, 34.14% yield, 96% purity) as an off-white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.43 (d, J = 2.8 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 10.1 Hz, 1H), 7.57 (dd, J = 2.9, 8.8 Hz, 1H), 7.13 - 7.00 (m, 3H), 4.79 - 4.74 (m, 2H), 4.73 - 4.65 (m, 2H), 4.26 (t, J = 5.2 Hz, 2H), 4.10 (s, 2H), 3.88 (t, J = 6.8 Hz, 2H), 3.12 (s, 6H), 3.03 (t, J = 5.1 Hz, 2H), 2.49 (s, 3H), 2.38 (t, J = 6.7 Hz, 2H). MS m/z (ESI) [M+H]+= 434.3. Attorney Docket No.: 185992002240 Example 140: (cis)-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4- c]pyridin-2-yl)-2-(4-piperazin-1-ylphenyl)quinoline
Figure imgf000413_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl 4-(4-(7- methoxy-4-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenyl)piperazine-1-carboxylate (700 mg, 1.26 mmol, 1 eq) in EtOAc (1 mL) was added HCl/EtOAc (2 M, 10 mL, 15.93 eq) at 20°C. The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient: 2-10 min 1-25%; flow 25 ml/min) basified by SCX cation exchange resin to give Example 140 (197.65 mg, 431.92 μmol, 34.41% yield, 100% purity) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15 (d, J = 9.4 Hz, 1H), 8.06 (d, J = 8.9 Hz, 2H), 7.22-7.21 (m, 1H), 7.01 (d, J = 8.9 Hz, 2H), 6.93 (dd, J = 2.8, 9.4 Hz, 1H), 6.80 (s, 1H), 3.89 (s, 3H), 3.83-3.82 (m, 2H), 3.70 - 3.69 (m, 1H), 3.58- 3.86 (m, 1H), 3.16 - 3.14 (m, 4H), 2.88 - 2.85 (m, 4H), 2.47 (s, 3H), 2.32-2.30 (m, 2H), 2.18 (s, 3H), 2.16 - 2.14 (m, 1H), 1.74 - 1.72 (m, 1H), 1.57 - 1.55 (m, 1H). MS m/z (ESI) [M+H]+= 458.3. Example 141: (cis)-N,N-dimethyl-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4- c]pyridin-2-yl)-2-[4-[2-(methylamino)ethoxy]phenyl]quinolin-7-amine
Figure imgf000413_0002
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of tert-butyl (2-(4-(7- (dimethylamino)-4-(cis-5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate (300 mg, 535.96 μmol, 1 eq) in DCM (4 mL) was added TFA (61.11 mg, 535.96 μmol, 39.81 μL, 1 eq). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated and the residue was purified by Attorney Docket No.: 185992002240 prep-HPLC 2 (gradient:0%-30% over 10 min) basified by SCX cation exchange resin to give Example 141 (55 mg, 119.66 μmol, 22.33% yield, 100% purity) as off-white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.23 (dd, J = 2.2, 9.6 Hz, 1H), 7.87 (br d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.09 - 7.03 (m, 1H), 7.01 (br s, 1H), 6.60 (br d, J = 3.4 Hz, 1H), 4.19 (t, J = 5.2 Hz, 2H), 3.92 (br s, 3H), 3.79 (br d, J = 9.9 Hz, 1H), 3.13 (s, 6H), 3.01 (t, J = 5.1 Hz, 2H), 2.66 - 2.51 (m, 4H), 2.49 (s, 3H), 2.47 - 2.35 (m, 2H), 2.32 (s, 3H), 1.92 - 1.83 (m, 1H), 1.76 - 1.66 (m, 1H). MS m/z (ESI) [M+H]+= 460.3. Example 142: N-methyl-2- [7-morpholino-4-(2-oxa-7- azaspiro[3.4]octan-7-yl)-2-
Figure imgf000414_0001
quinolyl]-3-pyridyl]oxy]ethanamine
Figure imgf000414_0002
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of C.2ag (90.0 mg, 0.100 mmol, 1 eq) in dichloromethane (5.00 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL) at 20°C. The mixture was stirred at 20°C for 12 hours and the residue was purified by prep-HPLC 3 (gradient:12%-42% over 12 min) basified by SCX cation exchange resin to give Example 142 (20.0 mg, 0.0409 mmol, 40.8% yield, 97.2% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.48 (d, J = 8.88 Hz, 1 H) 8.38 (d, J = 2.88 Hz, 1 H) 8.09 (d, J = 9.38 Hz, 1 H) 7.53 (dd, J = 8.82, 2.94 Hz, 1 H), 7.44 (s, 1 H), 7.24 - 7.14 (m, 2 H), 4.65 (d, J = 6.12 Hz, 2 H), 4.54 (d, J = 6.00 Hz, 2 H), 4.17 (t, J = 5.50 Hz, 2 H), 3.93 (s, 2 H), 3.84 - 3.76 (m, 4 H), 3.69 (s, 2 H), 3.30 - 3.24 (m, 4 H), 2.90 (t, J = 5.44 Hz, 2 H), 2.37 (s, 3 H), 2.29 (t, J = 6.64 Hz, 2 H). MS m/z (ESI) [M+H]+= 476.3. Example 153: 1-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-N- methyl-pyrrolidine-3-carboxamide
Figure imgf000414_0003
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl N-[2-[4- [6-fluoro-7-methoxy-4-[3-(methylcarbamoyl)pyrrolidin-1-yl]-2-quinolyl]phenoxy]ethyl]-N- Attorney Docket No.: 185992002240 methyl-carbamate (250 mg, 452.38 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M, 2 mL) at 25°C .The mixture was stirred at 25°C for 4hours. The reaction mixture was filtered and concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient:2%-32% over 9 min) basified by SCX cation exchange resin to give Example 153 (77.49 mg, 170.04 μmol, 37.59% yield, 99.3% purity). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.13 (d, J = 8.7 Hz, 2H), 8.02 (d, J = 4.6 Hz, 1H), 7.92 (d, J = 13.9 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.91 (s, 1H), 4.17 - 4.07 (m, 2H), 3.98 (s, 3H), 3.83 - 3.75 (m, 3H), 3.71 - 3.66 (m, 1H), 3.07 (q, J = 7.7 Hz, 1H), 2.93 - 2.86 (m, 2H), 2.63 (d, J = 4.5 Hz, 3H), 2.37 (s, 3H), 2.23 - 2.07 (m, 2H). MS m/z (ESI) [M+H]+= 453.2. Example 154: 6-fluoro-N,N-dimethyl-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4-(7- methyl-2,7-diazaspiro[4.4]nonan-2-yl)quinolin-7-amine
Figure imgf000415_0001
According to Scheme 3 Step 3: Conditions 1 HCl: A mixture of tert-butyl N-[2-[[5-[7- (dimethylamino)-6-fluoro-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-quinolyl]-2- pyridyl]oxy]ethyl]-N-methyl-carbamate (240 mg, 348.36 μmol, 1 eq) in HCl/MeOH (3 mL, 2M) was stirred at 20°C for 1hour. The mixture was concentrated to give a residue which was purified by prep-HPLC 1 (gradient: 1%-31% over 9 min) basified by SCX cation exchange resin to give Example 154 (82.78 mg, 172.96 μmol, 49.65% yield, 100% purity) as yellow gum. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (d, J = 2.3 Hz, 1H), 8.46 (dd, J = 2.4, 8.6 Hz, 1H), 7.85 (d, J = 16.3 Hz, 1H), 7.19 (d, J = 9.5 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.84 (s, 1H), 4.36 (t, J = 5.7 Hz, 2H), 3.74 (br t, J = 6.5 Hz, 2H), 3.70 - 3.59 (m, 2H), 2.94 - 2.84 (m, 8H), 2.62 - 2.53 (m, 2H), 2.48 - 2.44 (m, 1H), 2.40 (br d, J = 9.0 Hz, 1H), 2.35 (s, 3H), 2.23 (s, 3H), 2.05 - 1.74 (m, 4H). MS m/z (ESI) [M+H]+= 479.2. Example 156: 4-[3-(difluoromethoxy)pyrrolidin-1-yl]-N,N-dimethyl-2-[6-[2- (methylamino)ethoxy]-3-pyridyl]quinolin-7-amine
Figure imgf000415_0002
Attorney Docket No.: 185992002240 According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of tert-butyl N-[2- [[5-[4-[3-(difluoromethoxy)pyrrolidin-1-yl]-7-(dimethylamino)-2-quinolyl]-2- pyridyl]oxy]ethyl]-N-methyl-carbamate (200 mg, 358.66 μmol, 1 eq) in DCM (2 mL) was added TFA (40.90 mg, 358.66 μmol, 26.64 μL, 1 eq), then the resulting mixture was stirred at 25°C for 3 hours. The reaction mixture was filtered, evaporated under reduced pressure and the crude product was purified by prep-HPLC 2 (gradient:8%-38% over 10 min) basified by SCX cation exchange resin to give Example 156 (49.85 mg, 105.04 μmol, 29.29% yield, 96.4% purity) as a white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.68 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 2.5, 8.6 Hz, 1H), 8.14 (d, J = 9.4 Hz, 1H), 7.09 - 7.02 (m, 2H), 6.95 (d, J = 8.7 Hz, 1H), 6.69 (s, 1H), 6.63 (s, 1H), 6.50 (s, 1H), 6.32 (s, 1H), 5.02 (d, J = 2.6 Hz, 1H), 4.48 (t, J = 5.3 Hz, 2H), 4.13 (d, J = 4.5, 11.3 Hz, 1H), 4.00 (d, J = 8.7 Hz, 1H), 3.82 (d, J = 10.6 Hz, 2H), 3.10 (s, 6H), 3.01 (t, J = 5.4 Hz, 2H), 2.48 (s, 3H), 2.33 - 2.28 (m, 2H). MS m/z (ESI) [M+H]+= 458.2. Example 157: (cis)-2-[7-methoxy-2-(6-piperazin-1-yl-3-pyridyl)-4-quinolyl]-3,3a,5,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000416_0001
According to Scheme 3 Step 3: Conditions 1 HCl: Tert-butyl 4-(5-(7-methoxy-4-(cis- 4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2-yl)pyridin-2-yl)piperazine-1- carboxylate (200 mg, 357.99 μmol, 1 eq) was added to HCl/dioxane (2 M, 2 mL). The reaction solution was stirred at 25 °C for 1 hour. The reaction solution was concentrated under vacuum. The residue was purified by prep-HPLC 2 (gradient:0%-30% over 10 min) basified by SCX cation exchange resin to give Example 157 (20 mg, 42.52 μmol, 11.88% yield, 97.5% purity) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.63 (d, J = 2.4 Hz, 1H), 8.14 - 8.02 (m, 2H), 7.20 (d, J = 2.6 Hz, 1H), 6.94 (dd, J = 2.7, 9.4 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 6.68 (s, 1H), 4.00 - 3.87 (m, 3H), 3.84 (s, 3H), 3.59 - 3.50 (m, 5H), 3.40 - 3.26 (m, 2H), 3.07 (q, J = 7.8 Hz, 1H), 2.94 - 2.82 (m, 4H), 2.81 - 2.70 (m, 1H), 1.95 - 1.84 (m, 1H), 1.80 - 1.66 (m, 1H). MS m/z (ESI) [M+H]+= 459.2. Attorney Docket No.: 185992002240 Example 159: (cis)-2-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4- quinolyl]-3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000417_0001
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of cis-tert-butyl(2- (4-(6-fluoro-7-methoxy-4-(4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate (150 mg, 265.65 μmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 50.68 eq). Then the resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and evaporated under reduced pressure and the crude product was purified by prep-HPLC 10 (gradient:2%-32% over 10 min) basified by SCX cation exchange resin to give Example 159 (9.53 mg, 20.52 μmol, 7.72% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 7.96 - 7.91 (m, 3H), 7.46 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 6.89 (s, 1H), 4.25 (t, J = 5.1 Hz, 2H), 4.02 (s, 3H), 3.99 (br d, J = 4.3 Hz, 2H), 3.60 (d, J = 3.9, 10.1 Hz, 1H), 3.49 - 3.34 (m, 3H), 3.20 - 3.15 (m, 3H), 2.90 - 2.83 (m, 1H), 2.61 (s, 3H), 2.05 - 1.97 (m, 1H), 1.83 (d, J = 4.7, 9.5, 14.2 Hz, 1H). MS m/z (ESI) [M+H]+= 465.2. Example 160: 2-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-2,7- diazaspiro[4.5]decan-6-one
Figure imgf000417_0002
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl N-[2-[4- [6-fluoro-7-methoxy-4-(6-oxo-2,7-diazaspiro[4.5]decan-2-yl)-2-quinolyl]phenoxy]ethyl]-N- methyl-carbamate (125 mg, 216.01 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M, 2 mL) at 25°C. The mixture was stirred at 25 °C for 2hours. The reaction mixture was filtered and concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient:8%-38% over 9 min) basified by SCX cation exchange resin to give Example 160 (63.20 mg, 125.86 μmol, 58.26% yield, 95.3% purity). 1H NMR (400 MHz, DMSO-d6) δ Attorney Docket No.: 185992002240 (ppm): 8.15 (d, J = 8.9 Hz, 2H), 7.94 (d, J = 13.9 Hz, 1H), 7.61 (s, 1H), 7.42 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.91 (s, 1H), 4.13 (t, J = 5.3 Hz, 2H), 3.98 (s, 3H), 3.95 (d, J = 9.8 Hz, 1H), 3.92 - 3.85 (m, 1H), 3.80 - 3.72 (m, 1H), 3.61 (d, J = 9.7 Hz, 1H), 3.18 (s, 2H), 2.96 (t, J = 5.4 Hz, 2H), 2.44 - 2.36 (m, 4H), 1.98 - 1.90 (m, 1H), 1.89 - 1.73 (m, 4H). MS m/z (ESI) [M+H]+= 479.2. Example 161: (cis)-5-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4- quinolyl]-1,2,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-3-one
Figure imgf000418_0001
According to Scheme 4 Step 2: Conditions 2 TFA: To a solution of tert-butyl (2-(4-(6- fluoro-7-methoxy-4-(4-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate (180 mg, 326.90 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 41.18 eq). Then the resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and evaporated under reduced pressure and the crude product was purified by prep-HPLC 10 (gradient:8%-38% over 10 min) basified by SCX cation exchange resin to give Example 161 (12.88 mg, 28.25 μmol, 8.64% yield, 98.8% purity) as a white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 7.99 - 7.94 (m, 2H), 7.77 (d, J = 13.0 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.12 - 7.08 (m, 3H), 4.19 (t, J = 5.2 Hz, 2H), 4.02 (s, 3H), 3.99 (s, 1H), 3.76 (d, J = 7.3, 10.4 Hz, 1H), 3.71 - 3.65 (m, 1H), 3.58 (d, J = 3.4, 10.1 Hz, 1H), 3.50 (d, J = 6.8, 10.2 Hz, 1H), 3.38 (d, J = 1.6, 10.4 Hz, 1H), 3.27 - 3.19 (m, 2H), 3.04 (t, J = 5.1 Hz, 2H), 2.51 (s, 3H). MS m/z (ESI) [M+H]+= 451.2. Example 162: 2-[4-[4-(2,2-dioxo-2thia-7-azaspiro[3.4]octan-7-yl)-6-fluoro-7-methoxy-2- quinolyl]phenoxy]-N-methyl-ethanamine
Figure imgf000418_0002
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl N-[2-[4- [4-(2,2-dioxo-2thia-7-azaspiro[3.4]octan-7-yl)-6-fluoro-7-methoxy-2- Attorney Docket No.: 185992002240 quinolyl]phenoxy]ethyl]-N-methyl-carbamate (160 mg, 273.18 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M, 2 mL) at 25°C. The mixture was stirred at 25°C for 2hours. The reaction mixture was filtered and concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient:2%-32% over 9 min) basified by SCX cation exchange resin to give Example 162 (88.01 mg, 181.25 μmol, 66.35% yield, 100% purity). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.13 (d, J = 8.9 Hz, 2H), 7.90 (d, J = 14.0 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 8.9 Hz, 2H), 6.92 (s, 1H), 4.39 - 4.33 (m, 2H), 4.26 - 4.20 (m, 2H), 4.09 (t, J = 5.6 Hz, 2H), 3.99 (s, 5H), 3.79 (t, J = 6.5 Hz, 2H), 2.88 (t, J = 5.5 Hz, 2H), 2.37 (s, 3H), 2.31 (t, J = 6.3 Hz, 2H). MS m/z (ESI) [M+H]+= 486.1. Example 164: (cis)-N'-[5-[6-fluoro-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H- pyrrolo[3,4-c]pyridin-2-yl)-2-quinolyl]-2-pyridyl]-N,N'-dimethyl-ethane-1,2-diamine
Figure imgf000419_0001
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of tert-butyl tert- butyl(2-((5-(6-fluoro-7-methoxy-4-(5-methyloctahydro-2H- pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)pyridin-2-yl)(methyl)amino)ethyl)(methyl)carbamate (300 mg, 0.487 mmol, 1 eq) in dichloromethane (5.00 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 27.6 eq) at 20°C. The mixture was stirred at 20°C for 12 hours. The reaction mixture was concentrated under reduce pressure and the residue was purified by prep-HPLC 3 (gradient:2%-32% over 12 min) basified by SCX cation exchange resin to give Example 164 (130 mg, 0.272 mmol, 55.7% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.88 (d, J = 2.32 Hz, 1 H), 8.28 (dd, J = 8.99, 2.38 Hz, 1 H), 7.95 (d, J = 14.06 Hz, 1 H), 7.37 (d, J = 9.05 Hz, 1 H), 6.82 (s, 1 H), 6.70 (d, J = 9.05 Hz, 1 H), 4.04 – 3.92 (m, 3 H), 3.84 - 3.71 (m, 3 H), 3.66 ( t, J = 6.66 Hz, 2 H), 3.58 ( dd, J = 9.78, 4.40 Hz, 1 H), 3.08 (s, 3 H), 2.73 (t, J = 6.66 Hz, 2 H), 2.49 - 2.38 (m, 3 H), 2.34 (s, 3 H), 2.33 - 2.24 (m, 2 H), 2.17 (s, 3 H), 2.15 - 2.07 (m, 1 H), 1.70 ( d, J = 6.11 Hz, 1 H), 1.56 ( dd, J = 8.68, 4.03 Hz, 1 H). MS m/z (ESI) [M+H]+= 479.4. Attorney Docket No.: 185992002240 Example 165: (cis)-2-[6-fluoro-7-methoxy-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4- quinolyl]- hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000420_0001
Figure imgf000420_0002
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl (2-((5- (6-fluoro-7-methoxy-4-(cis-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate (70 mg, 123.75 μmol, 1 eq) in MeOH (0.5 mL) was added HCl/MeOH (2 M, 1 mL) at 25°C .The mixture was stirred at 25°C for 2hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC 1 (gradient:3%-33% over 9 min) basified by SCX cation exchange resin to give Example 165 (16.54 mg, 35.53 μmol, 28.71% yield, 100% purity). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.96 (d, J = 2.2 Hz, 1H), 8.50 (dd, J = 2.4, 8.7 Hz, 1H), 7.99 (d, J = 13.9 Hz, 1H), 7.74 s, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.00 (s, 1H), 6.92 (d, J = 8.6 Hz, 1H), 4.39 (t, J = 5.6 Hz, 2H), 4.01 - 3.95 (m, 4H), 3.92 - 3.83 (m, 2H), 3.56 (dd, J = 5.1, 10.0 Hz, 1H), 3.28 - 3.17 (m, 2H), 3.03 - 2.97 (m, 1H), 2.92 (t, J = 5.6 Hz, 2H), 2.76 (d, J = 3.2 Hz, 1H), 2.38 (s, 3H), 1.94 - 1.85 (m, 1H), 1.74 - 1.64 (m, 1H). MS m/z (ESI) [M+H]+= 466.2. Example 169: (cis)-2-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4- quinolyl]-70methyl-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one
Figure imgf000420_0003
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of tert-butyl (2-(4-(6- fluoro-7-methoxy-4-(cis-5-methyl-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate (250 mg, 432.02 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 31.16 eq), then the resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered and evaporated under reduced pressure and the crude product was purified by prep-HPLC 10 (gradient:5%-35% over 10 min ) basified by Attorney Docket No.: 185992002240 SCX cation exchange resin to give Example 169 (73.94 mg, 154.51 μmol, 35.76% yield, 100% purity) as a white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 7.96 - 7.88 (m, 3H), 7.45 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.86 (s, 1H), 4.20 (t, J = 5.1 Hz, 2H), 4.04 - 3.94 (m, 6H), 3.59 (d, J = 3.4, 10.0 Hz, 1H), 3.55 - 3.46 (m, 2H), 3.19 (d, J = 7.7 Hz, 1H), 3.08 (t, J = 5.1 Hz, 2H), 3.01 (s, 3H), 2.89 - 2.80 (m, 1H), 2.54 (s, 3H), 2.05 - 1.86 (m, 2H). MS m/z (ESI) [M+H]+= 479.2 Example 170: (cis)-2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-5- methyl-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one
Figure imgf000421_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl (2-(4-(7- methoxy-4-cis-5-methyl-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate (200 mg, 356.71 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M, 178.35 μL) at 25°C .The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by prep- HPLC 1 (gradient:6%-36% over 9 min) basified by SCX cation exchange resin to give Example 170 (138.46 mg, 300.63 μmol, 84.28% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.19 - 8.11 (m, 3H), 7.25 (d, J = 2.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.98 (dd, J = 2.8, 9.4 Hz, 1H), 6.90 (s, 1H), 4.08 (t, J = 5.6 Hz, 2H), 3.99 - 3.94 (m, 1H), 3.93 - 3.86 (m, 5H), 3.57 (dd, J = 4.8, 10.1 Hz, 1H), 3.41 ( t, J = 5.8 Hz, 2H), 3.09 - 3.03 (m, 1H), 2.90 - 2.84 (m, 5H), 2.81 - 2.72 (m, 1H), 2.36 (s, 3H), 1.98 - 1.91 (m, 1H), 1.84 - 1.74 (m, 1H). MS m/z (ESI) [M+H]+= 461.3. Example 175: 1-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]- N,N-dimethyl-pyrrolidine-3-carboxamide
Figure imgf000421_0002
Attorney Docket No.: 185992002240 According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl N-[2-[4- [4-[3-(dimethylcarbamoyl)pyrrolidin-1-yl]-6-fluoro-7-methoxy-2-quinolyl]phenoxy]ethyl]- N-methyl-carbamate (280 mg, 494.12 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M, 247.06 μl, 1.00 eq) at 25°C .The mixture was stirred at 25°C for 4hours. The reaction mixture was filtered and concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient:7%-37% over 9 min) basified by SCX cation exchange resin to give Example 175 (95.41 mg, 204.50 μmol, 41.39% yield, 100% purity). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.14 (d, J = 8.9 Hz, 2H), 7.95 (d, J = 13.9 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.94 (s, 1H), 4.11 (t, J = 5.5 Hz, 2H), 3.99 (s, 3H), 3.82 (d, J = 7.1 Hz, 2H), 3.79 - 3.73 (m, 1H), 3.72 - 3.65 (m, 1H), 3.56 - 3.51 (m, 1H), 3.09 (s, 3H), 2.93 (t, J = 5.5 Hz, 2H), 2.87 (s, 3H), 2.40 (s, 3H), 2.29 - 2.19 (m, 1H), 2.15 - 2.05 (m, 1H). MS m/z (ESI) [M+H]+= 467.2. Example 176: (cis)-2-[7-(dimethylamino)-2-[6-[2-(methylamino)ethoxy]-3-pyridyl]-4- quinolyl]-5-methyl-1,3,3a,6,7,7a- 4-one
Figure imgf000422_0001
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of tert-butyl (2-((5- (7-(dimethylamino)-4-((cis)-5-methyl-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate (250 mg, 435.00 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 30.95 eq) , then the resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and evaporated under reduced pressure and the crude product was purified by prep-HPLC 10 (gradient:2%- 32% over 10 min ) basified by SCX cation exchange resin to give Example 176 (91 mg, 191.74 μmol, 44.08% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, methanol- d4) δ (ppm): 8.69 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 2.5, 8.6 Hz, 1H), 8.14 (d, J = 9.4 Hz, 1H), 7.07 (d, J = 2.7, 9.4 Hz, 1H), 7.03 (d, J = 2.6 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.65 (s, 1H), 4.51 - 4.46 (m, 2H), 4.09 - 4.00 (m, 3H), 3.65 (d, J = 3.5, 10.3 Hz, 1H), 3.54 - 3.46 (m, 2H), 3.18 (d, J = 7.6 Hz, 1H), 3.10 (s, 6H), 3.03 - 2.99 (m, 5H), 2.88 - 2.81 (m, 1H), 2.49 (s, 3H), 2.05 - 1.98 (m, 1H), 1.92 (td, J = 4.7, 9.4 Hz, 1H). MS m/z (ESI) [M+H]+= 475.4. Attorney Docket No.: 185992002240 Example 178: (cis)-2-[4-[4-(2,2-dioxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-c]pyrrol-5-yl)-6- fluoro-7-methoxy-2-quinolyl]phenoxy]-N-methyl-ethanamine
Figure imgf000423_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl N-[2-[4- [4-(2,2-dioxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-c]pyrrol-5-yl)-6-fluoro-7-methoxy-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate (150 mg, 256.11 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M, 1 mL) at 25°C .The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient:5%-35% over 9 min) basified by SCX cation exchange resin to give Example 178 (76.03 mg, 156.58 μmol, 61.14% yield, 100% purity) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 13.2 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.11 (s, 1H), 7.06 (d, J = 8.8 Hz, 2H), 4.10 (t, J = 5.6 Hz, 2H), 3.99 (s, 3H), 3.87 ( dd, J = 6.2, 10.2 Hz, 2H), 3.57 (b dd, J = 3.8, 10.2 Hz, 2H), 3.42 ( d, J = 5.2 Hz, 2H), 3.25 - 3.20 (m, 4H), 2.88 (t, J = 5.6 Hz, 2H), 2.37 (s, 3H). MS m/z (ESI) [M+H]+= 486.3. Example 180: (cis)-2-[2-[4-(azetidin-3-yloxy)phenyl]-6-fluoro-7-methoxy-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000423_0002
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of cis-tert-butyl 3-(4- (6-fluoro-7-methoxy-4-(4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)azetidine-1-carboxylate (140 mg, 248.8 μmol, 1 eq) in EtOAc (0.50 mL) was added HCl/EtOAc (2 M, 3.00 mL, 24.1 eq) at 20°C. The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient: 2-9 min 5-35%; flow 25 mL/min) basified by SCX cation exchange resin to give Example 180 (45.07 mg, 97.5 μmol, 39.2% yield) as a white Attorney Docket No.: 185992002240 solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.14 (br d, J = 8.6 Hz, 2H), 7.97 (d, J = 13.8 Hz, 1H), 7.75 (br s, 1H), 7.44 (d, J = 8.9 Hz, 1H), 6.97 (s, 1H), 6.91 (br d, J = 8.6 Hz, 2H), 5.14 - 4.98 (m, 1H), 3.99 (s, 3H), 3.96 - 3.77 (m, 5H), 3.57 - 3.51 (m, 3H), 3.26 - 3.18 (m, 2H), 3.01 (br d, J = 7.3 Hz, 1H), 2.80 - 2.75 (m, 1H), 1.95 - 1.86 (m, 1H), 1.69 (br d, J = 9.1 Hz, 1H). MS m/z (ESI) [M+H]+= 463.2. Example 181: (cis)-2-[6-fluoro-7-methoxy-2-(4-pyrrolidin-3-yloxyphenyl)-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000424_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of cis-tert-butyl 3-(4- (6-fluoro-7-methoxy-4-(4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)pyrrolidine-1-carboxylate (200 mg, 347 μmol, 1 eq) in EtOAc (0.500 mL) was added HCl/EtOAc (2 M, 5.00 mL, 28.8 eq) at 20°C. The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient: 2-9 min 3-33%; flow 25 mL/min) basified by SCX cation exchange resin to give Example 181 (43.12 mg, 89.9 μmol, 25.9% yield, 99.4% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15 (br d, J = 8.8 Hz, 2H), 7.97 (d, J = 14.0 Hz, 1H), 7.76 (br s, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.07 - 6.94 (m, 3H), 4.99 (br s, 1H), 4.00 (s, 3H), 3.96 - 3.80 (m, 3H), 3.56 - 3.52 (m, 1H), 3.25 - 3.11 (m, 3H), 3.06 - 2.85 (m, 4H), 2.82 - 2.72 (m, 1H), 2.10 (br dd, J = 6.3, 13.8 Hz, 1H), 1.97 - 1.81 (m, 2H), 1.77 - 1.61 (m, 1H). MS m/z (ESI) [M+H]+= 472.2. Example 187: (cis)-2-[4-[4-(7,7-difluoro-5-methyl-1,3,3a,4,6,7a-hexahydropyrrolo[3,4- c]pyridin-2-yl)-6-fluoro-7-methoxy-2-quinolyl]phenoxy]-N-methyl-ethanamine
Figure imgf000424_0002
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl (2-(4-(4- (cis-7,7-difluoro-5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-6-fluoro-7- Attorney Docket No.: 185992002240 methoxyquinolin-2-yl)phenoxy)ethyl)(methyl)carbamate (50 mg, 83.24 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M, 1 mL) at 25°C. The mixture was stirred at 25°C for 2 hours. The residue was purified by prep-TLC (Plate 1, SiO2, Dichloromethane : Methanol= 10:1) to give Example 187 (23.5 mg, 46.95 μmol, 56.40% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 7.95 - 7.87 (m, 3H), 7.43 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.78 (s, 1H), 4.20 (t, J = 5.2 Hz, 2H), 4.03 - 3.96 (m, 4H), 3.94 - 3.85 (m, 2H), 3.73 - 3.66 (m, 1H), 3.07 (t, J = 5.2 Hz, 2H), 2.94 - 2.69 (m, 4H), 2.64 ( dd, J = 4.2, 12.2 Hz, 1H), 2.53 (s, 3H), 2.46 ( dd, J = 8.8, 12.2 Hz, 1H), 2.37 (s, 3H). MS m/z (ESI) [M+H]+= 501.2. Example 190: (cis)-2-[6-(azetidin-3-ylmethoxy)-3-pyridyl]-6-fluoro-7-methoxy-4-(5-methyl- 3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)quinoline
Figure imgf000425_0001
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of tert-butyl 3-(((5- (6-fluoro-7-methoxy-4-(cis-5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)pyridin-2-yl)oxy)methyl)azetidine-1-carboxylate (120 mg, 207.72 μmol, 1 eq) in DCM (1 mL) was added TFA (307.00 mg, 2.69 mmol, 0.2 mL, 12.96 eq) at 25°C . After stirring at 25°C for 2 hours, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC 2 (gradient:1%-20% over 10 min) basified by SCX cation exchange resin to give Example 190 (25 mg, 51.82 μmol, 24.95% yield, 99% purity)  as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.94 (d, J = 2.0 Hz, 1H), 8.55 - 8.41 (m, 1H), 8.00 (d, J = 14.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.99 - 6.82 (m, 2H), 4.51 - 4.42 (m, 2H), 3.98 (s, 3H), 3.96-3.94 (m, 5H), 3.69 - 3.55 (m, 4H), 2.46 - 2.23 (m, 5H), 2.22 - 2.11 (m, 4H), 1.83 - 1.63 (m, 1H), 1.46 - 1.44 (m, 1H). MS m/z (ESI) [M+H]+= 478.3. Attorney Docket No.: 185992002240 Example 195: 2-[4-[6-fluoro-7-methoxy-4-(2-methyl-2, 6-diazaspiro[3.4]octan-6-yl) -2- quinolyl]phenoxy]-N-methyl-ethanamine
Figure imgf000426_0001
According to Scheme 3 Step 3: Conditions 2 TFA: A solution of tert-butyl N-[2-[4-[6- fluoro-7-methoxy-4-(2-methyl-2, 6-diazaspiro[3.4]octan-6-yl) -2-quinolyl]phenoxy]ethyl]-N- methyl-carbamate (250 mg, 454.00 μmol, 1 eq) in TFA (1 mL)/DCM (3 mL) was stirred at 25°C for 2 hours then the reaction mixture was concentrated and the crude material was purified by Prep-HPLC 10 (gradient:1%-20% over 10 min) basified by SCX cation exchange resin to give Example 195 (110 mg, 244.15 μmol, 53.78% yield, 100% purity) as white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.12 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 13.9 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.88 (s, 1H), 4.08 (t, J = 5.6 Hz, 2H), 3.98 (s, 3H), 3.79 (s, 2H), 3.69 (br t, J = 6.5 Hz, 2H), 3.17 (d, J = 6.8 Hz, 2H), 3.13 (d, J = 6.8 Hz, 2H), 2.85 (t, J = 5.6 Hz, 2H), 2.35 (s, 3H), 2.23 (s, 3H), 2.13 (br t, J = 6.6 Hz, 2H). MS m/z (ESI) [M+H]+= 451.3. Example 205: (cis)-2-[4-[6-fluoro-7-methoxy-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H- pyrrolo[3,4-c]pyridin-2-yl)-2-quinolyl]phenyl]sulfanyl-N-methyl-ethanamine
Figure imgf000426_0002
According to Scheme 3 Step 3: Conditions 1 HCl: A mixture of cis-tert-butyl (2-((4- (6-fluoro-7-methoxy-4-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenyl)thio)ethyl)(methyl)carbamate (180 mg, 213.86 μmol, 1 eq) in HCl/dioxane (3 mL, 2M) was stirred at 25°C for 1hour then mixture was concentrated and the residue was purified by prep-HPLC 1 (gradient: 0%-30% over 10 min), basified by SCX cation exchange resin to give Example 205 (50.83 mg, 105.76 μmol, 49.45% yield, 100% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.12 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 14.1 Hz, 1H), 7.42 (br d, J = 8.1 Hz, 3H), 6.87 (s, 1H), 3.98 (s, 3H), 3.87 - 3.68 (m, 3H), 3.59 (br dd, J Attorney Docket No.: 185992002240 = 4.3, 9.7 Hz, 1H), 3.40 (br d, J = 6.5 Hz, 2H), 3.11 (t, J = 6.9 Hz, 2H), 2.77 - 2.65 (m, 2H), 2.46 (br d, J = 7.0 Hz, 2H), 2.30 (s, 5H), 2.20 - 2.07 (m, 4H), 1.70 (br d, J = 10.5 Hz, 1H), 1.61 - 1.47 (m, 1H). MS m/z (ESI) [M+H]+= 481.2. Example 206: (cis)-6-fluoro-2-[4-(1H-imidazol-4-yloxy)phenyl]-7-methoxy-4-(5-methyl- 3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)quinoline
Figure imgf000427_0001
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of 6-fluoro-7- methoxy-4-(cis-5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-2-(4-((1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)oxy)phenyl)quinoline (290 mg, 480.29 μmol, 1 eq) in DCM (2 mL) was added TFA (54.76 mg, 480.29 μmol, 35.68 μL, 1 eq). Then the resulting mixture was stirred at 25°C for 2 hours, filtered and evaporated under reduced and the residue was purified by prep-HPLC 1 (gradient:0%-26% over 10 min ) basified by SCX cation exchange resin to give Example 206 (207.97 mg, 439.18 μmol, 91.44% yield, 100% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 14.21 (br d, J = 6.9 Hz, 1H), 11.16 (d, J = 1.6, 5.1 Hz, 1H), 8.58 (br d, J = 7.8 Hz, 1H), 8.37 - 8.19 (m, 4H), 7.42 - 7.32 (m, 3H), 6.83 (s, 1H), 4.00 (br d, J = 1.9 Hz, 4H), 3.75 - 3.52 (m, 2H), 3.30 (br d, J = 13.1 Hz, 2H), 3.09 - 2.84 (m, 2H), 2.73 (d, J = 4.0, 14.0 Hz, 4H), 2.60 - 2.51 (m, 2H), 2.37 - 1.79 (m, 2H). MS m/z (ESI) [M+H]+= 474.3. Example 207: (cis)-2-[6-fluoro-7-methoxy-2-(6-piperazin-1-yl-3-pyridyl)-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000427_0002
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl 4-(5-(6- fluoro-7-methoxy-4-(cis-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)pyridin-2-yl)piperazine-1-carboxylate (160 mg, 141.85 μmol, 1 eq) in dioxane (1 mL) was Attorney Docket No.: 185992002240 added HCl/dioxane (2 M, 1 mL) at 25°C.The mixture was stirred at 25°C for 2hours then concentrated under reduced pressure and the residue was purified by prep-HPLC 3 (gradient: 8%-38% B over 12 min) basified by SCX cation exchange resin to give Example 207 (10 mg, 20.98 μmol, 14.79% yield, 100% purity) as a white solid. 1H NMR (400 MHz, DMSO- d6) δ (ppm): 8.94 (d, J = 2.2 Hz, 1H), 8.34 (dd, J = 2.4, 8.8 Hz, 1H), 7.94 (d, J = 13.8 Hz, 1H), 7.74 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.01 - 3.92 (m, 4H), 3.90 - 3.77 (m, 2H), 3.58 - 3.48 (m, 5H), 3.27 - 3.17 (m, 2H), 3.05 - 2.95 (m, 1H), 2.92 - 2.69 (m, 5H), 1.95 - 1.83 (m, 1H), 1.75 - 1.63 (m, 1H). MS m/z (ESI) [M+H]+= 477.2. Example 209: 6-fluoro-4-(3-methoxypyrrolidin-1-yl)-N,N-dimethyl-2-[4-[2- (methylamino)ethoxy]phenyl]quinolin-7-amine
Figure imgf000428_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl N-[2-[4- [7-(dimethylamino)-6-fluoro-4-(3-methoxypyrrolidin-1-yl)-2-quinolyl]phenoxy]ethyl]-N- methyl-carbamate (200 mg, 371.30 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M, 1 mL) at 25°C. After stirring at 25°C for 2 hours the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient: 9%-39% over 10 min) basified by SCX cation exchange resin to give Example 209 (50 mg, 114.02 μmol, 30.71% yield, 100% purity) as yellow gum. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.11 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 16.4 Hz, 1H), 7.20 (d, J = 9.6 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.84 (s, 1H), 4.17 - 4.04 (m, 3H), 3.94 (dd, J = 4.4, 10.8 Hz, 1H), 3.84 - 3.75 (m, 1H), 3.91 - 3.64 (m, 1H), 3.67 - 3.59 (m, 2H), 3.28 (s, 3H), 2.92 (s, 6H), 2.86 (t, J = 5.6 Hz, 2H), 2.36 (s, 3H), 2.19 - 2.01 (m, 2H). MS m/z (ESI) [M+H]+= 439.3. Example 217: -1-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-
Figure imgf000428_0002
quinolyl]-N-methyl-pyrrolidine-3-carboxamide
Figure imgf000428_0003
Attorney Docket No.: 185992002240 According to Scheme 3 Step 3: Conditions 2 TFA: A solution of tert-butyl N-[2-[4-[6- fluoro-7-methoxy-4-[(3S) -3-(methylcarbamoyl) pyrrolidin-1-yl]-2-quinolyl]phenoxy]ethyl]- N-methyl-carbamate (220 mg, 398.09 μmol, 1 eq) in TFA (1 mL)/DCM (3 mL) was stirred at 25°C for 1 hour then mixture was concentrated and the residue was purified by prep-HPLC 1 (gradient: 0%-30% over 10 min), basified by SCX cation exchange resin to give Example 217 (80 mg, 174.31 μmol, 43.79% yield, 98.6% purity) as white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.13 (d, J = 8.9 Hz, 2H), 8.05 - 7.99 (m, 1H), 7.93 (d, J = 13.9 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.91 (s, 1H), 4.10 (t, J = 5.6 Hz, 2H), 3.98 (s, 3H), 3.85 - 3.75 (m, 3H), 3.73 - 3.66 (m, 1H), 3.13 - 3.03 (m, 1H), 2.90 (t, J = 5.6 Hz, 2H), 2.63 (d, J = 4.6 Hz, 3H), 2.27 - 2.06 (m, 2H). MS m/z (ESI) [M+H]+= 453.2. Example 224: 2-[4-[6-fluoro-7-methoxy-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)-2- quinolyl]phenoxy]-N-methyl-ethanamine
Figure imgf000429_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl N-[2-[4- [6-fluoro-7-methoxy-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)-2-quinolyl]phenoxy]ethyl]-N- methyl-carbamate (200 mg, 372.01 μmol, 1 eq) in DCM (2.5 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 18.09 eq) at 25°C. The mixture was stirred at 25°C for 1 hour then filtered and concentrated under reduced pressure and the residue was purified by prep-HPLC 3 (gradient: 10%-40% B over 10 min) basified by SCX cation exchange resin to give Example 224 (116.67 mg, 266.67 μmol, 71.68% yield, 100% purity). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.13 (d, J = 8.7 Hz, 2H), 7.93 (d, J = 13.8 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 6.91 (s, 1H), 4.65 (d, J = 6.0 Hz, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.09 (t, J = 5.6 Hz, 2H), 3.98 (s, 3H), 3.95 (s, 2H), 3.71 (t, J = 6.5 Hz, 2H), 2.88 (t, J = 5.5 Hz, 2H), 2.37 (s, 3H), 2.28 (t, J = 6.6 Hz, 2H). MS m/z (ESI) [M+H]+= 438.2. Attorney Docket No.: 185992002240 Example 229: [1-[6-fluoro-2-[5-[2-(methylamino)ethoxy]-2-pyridyl]-7-(trideuteriomethoxy)- 4-quinolyl]pyrrolidin-3-yl]methanol
Figure imgf000430_0001
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of tert-butyl N-[2- [[6-[6-fluoro-4-[3-(hydroxymethyl)pyrrolidin-1-yl]-7-(trideuteriomethoxy)-2-quinolyl]-3- pyridyl]oxy]ethyl]-N-methyl-carbamate (180 mg, 339.87 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 39.61 eq). The resulting mixture was stirred at 25°C for 2 hours then filtered and evaporated under reduced pressure and the crude product was purified by prep-HPLC 2 (gradient:2%-30% over 10 min) basified by SCX cation exchange resin to give Example 229 (57.24 mg, 132.60 μmol, 39.02% yield, 99.5% purity) as a white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.38 (d, J = 2.7 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 13.8 Hz, 1H), 7.56 (d, J = 2.9, 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 4.26 (t, J = 5.1 Hz, 2H), 3.86 - 3.78 (m, 3H), 3.71 - 3.61 (m, 3H), 3.04 (t, J = 5.1 Hz, 2H), 2.61 - 2.54 (m, 1H), 2.50 (s, 3H), 2.19 (d, J = 5.4, 11.8 Hz, 1H), 1.88 (br s, 1H). MS m/z (ESI) [M+H]+= 430.2. Example 231: (cis)-2-[4-[6-fluoro-4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4- c]pyridin-2-yl)-7-(trideuteriomethoxy)-2-quinolyl]phenoxy]-N-methyl-ethanamine
Figure imgf000430_0002
According to Scheme 3 Step 3: Conditions 1 HCl: cis-tert-butyl (2-(4-(6-fluoro-7- (methoxy-d3)-4-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate was added to HCl/dioxane (2 M, 1 mL, 11.35 eq), the reaction mixture was stirred at 25°C for 1 hour, concentrated and the residue was purified by prep-HPLC 1 (gradient:0%-26% over 10 min) basified by SCX cation exchange resin to give Example 231 (50.88 mg, 108.81 μmol, 61.77% yield, 100% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 14.06 - 13.69 (m, 1H), 11.12 - 10.84 (m, 1H), 9.45 - 9.08 (m, 2H), 8.51 - 7.93 (m, 4H), 7.25 (br d, J = 7.9 Hz, 2H), 6.85 (s, 1H), 4.42 (br t, J = 4.8 Attorney Docket No.: 185992002240 Hz, 2H), 4.09 - 3.47 (m, 4H), 3.33 - 3.22 (m, 4H), 3.07 - 2.80 (m, 2H), 2.78 - 2.69 (m, 3H), 2.64 (br s, 5H), 2.35 (s, 2H). MS m/z (ESI) [M+H]+= 468.3. Example 233: (cis)-5-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4- quinolyl]-1,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-2-one
Figure imgf000431_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl N-[2-[4- [6-fluoro-7-methoxy-4-(2-oxo-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-b]pyrrol-5-yl)-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate (150 mg, 266.97 μmol, 1 eq) in dioxane (3 mL)was added HCl/dioxane (2 M, 2 mL, 14.98 eq) at 20°C. The mixture was stirred at 20 °C for 2 hours concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient:0%-30% over 10 min) basified by SCX cation exchange resin to give Example 233 (40 mg, 88.79 μmol, 33.26% yield, 100% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.16 (d, J=8.80 Hz, 2 H), 7.91 (s, 1 H), 7.79 (d, J=13.20 Hz, 1 H), 7.49 (d, J=8.68 Hz, 1 H), 7.15 (s, 1 H), 7.06 (d, J=8.80 Hz, 2 H), 4.31 - 4.22 (m, 1 H), 4.11 ( t, J=5.44 Hz, 2 H), 4.00 (s, 3 H), 3.64 (d, J=10.64 Hz, 1 H), 3.57 - 3.49 (m, 2 H), 3.42 (d, J = 4.78 Hz, 1 H), 3.15 - 3.04 (m, 1 H), 2.91 ( t, J=5.40 Hz, 2 H), 2.59 ( dd, J=17.2, 9.28 Hz, 1 H), 2.39 (s, 3 H),2.21(dd, J=17.12, 2.32 Hz, 1 H). MS m/z (ESI) [M+H]+= 451.3. Example 236: (3aS,7aR)-2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000431_0002
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl (2-(4-(7- methoxy-4-((3aS,7aR)-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate (150 mg, 274.40 μmol, 1 eq) in MeOH (2 mL) was added HCl/dioxane (2 M, 2 mL, 14.58 eq). The reaction solution was stirred at 25 °C for 1 hour, concentrated under vacuum and the residue was purified by prep-HPLC 1 (radient:6%- Attorney Docket No.: 185992002240 36% over 10 min) basified by SCX cation exchange resin to give Example 236 (60 mg, 134.37 μmol, 48.97% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.44 (s, 1H), 9.18 (br d, J = 6.5 Hz, 2H), 8.48 (d, J = 9.7 Hz, 1H), 8.12 (d, J = 8.9 Hz, 2H), 7.92 - 7.71 (m, 2H), 7.33 - 7.15 (m, 3H), 6.85 (s, 1H), 4.41 (t, J = 5.0 Hz, 2H), 4.34 - 4.14 (m, 3H), 4.02 - 3.86 (m, 4H), 3.43 - 3.24 (m, 4H), 3.16 - 3.07 (m, 1H), 2.91 - 2.80 (m, 1H), 2.67 - 2.62 (m, 3H), 1.99 - 1.87 (m, 1H), 1.79 - 1.66 (m, 1H). MS m/z (ESI) [M+H]+= 447.3. Example 239: (cis)-2-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-6-fluoro-7-methoxy-4- quinolyl]-5-methyl-1,3,3a,6,7,7a- 4-one
Figure imgf000432_0001
According to Scheme 1 Step 5: A mixture of 2-[4-(4-chloro-6-fluoro-7-methoxy-2- quinolyl)phenoxy]-N,N-dimethyl-ethanamine (200 mg, 533.57 μmol, 1 eq), cis-5- methyloctahydro-4H-pyrrolo[3,4-c]pyridin-4-one (123 mg, 797.62 μmol, 1.49 eq), SPhos Pd G3 (42 mg, 53.83 μmol, 1.01e-1 eq) and Cs2CO3 (522 mg, 1.60 mmol, 3 eq) in dioxane (5 mL) was stirred at 80 °C for 12h under N2. The mixture was diluted with EtOAc (15 ml), and then filtered. The filtrate was concentrated to give a residue which was purified by prep- HPLC 1 (gradient: 5%-35% over 10 min) to give Example 239 (50.86 mg, 89.94 μmol, 16.86% yield, 100% purity, 2HCl) as yellow gum. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.82 (br s, 1H), 10.83 (br s, 1H), 8.30 (br d, J = 13.5 Hz, 1H), 8.22 - 8.11 (m, 3H), 7.25 (br d, J = 8.6 Hz, 2H), 6.85 (s, 1H), 4.51 (br s, 2H), 4.32 - 4.14 (m, 3H), 4.06 - 3.91 (m, 4H), 3.48 - 3.35 (m, 3H), 3.14 (br d, J = 6.6 Hz, 1H), 2.96 - 2.78 (m, 11H), 2.04 - 1.92 (m, 1H), 1.89 - 1.78 (m, 1H). MS m/z (ESI) [M+H]+= 493.2. Attorney Docket No.: 185992002240 Example 242: (cis)-2-[2-[4-(azetidin-3-yloxy)phenyl]-6-fluoro-7-methoxy-4-quinolyl]-5- methyl-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one
Figure imgf000433_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of cis-tert-butyl 3-(4- (6-fluoro-7-methoxy-4-(5-methyl-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)azetidine-1-carboxylate (120 mg, 208.10 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 M, 1 mL) at 25 °C. The mixture was stirred at 25 °C for 2 hours, concentrated under reduced pressure and the residue was purified by prep-HPLC 1 (gradient:2%-32% over 10 min) basified by SCX cation exchange resin to give Example 242 (54.93 mg, 115.27 μmol, 55.39% yield, 100% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.85 ( s, 1H), 9.76 - 9.49 (m, 2H), 8.32 (d, J = 13.2 Hz, 1H), 8.19 - 8.10 (m, 3H), 7.13 (d, J = 8.8 Hz, 2H), 6.86 (s, 1H), 5.29 - 5.19 (m, 1H), 4.56 - 4.45 (m, 2H), 4.32 - 4.15 (m, 3H), 4.08 - 3.94 (m, 6H), 3.45 - 3.41 (m, 2H), 3.14 (q, J = 6.9 Hz, 1H), 2.90 - 2.82 (m, 4H), 2.03 - 1.92 (m, 1H), 1.89 - 1.77 (m, 1H). MS m/z (ESI) [M+H]+= 477.2. Example 246: 2-[4-[6-fluoro-7-methoxy-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-2- quinolyl]phenoxy]-N-methyl-ethanamine
Figure imgf000433_0002
According to Scheme 3 Step 3: Conditions 1 HCl: A mixture of tert-butyl N-[2-[4-[6- fluoro-7-methoxy-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-quinolyl]phenoxy]ethyl]-N- methyl-carbamate (150 mg, 265.63 μmol, 1 eq) in HCl/dioxane (2 M, 3 mL) was stirred at 25 °C for 1hour, concentrated and the residue was purified by prep-HPLC 1 (gradient: 0%-26% over 10 min) to give Example 246 (104.56 mg, 182.17 μmol, 68.58% yield, 100% purity, 3HCl) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.95 (br d, J = 13.9 Hz, 1H), 11.74 - 11.45 (m, 1H), 9.38 (br s, 2H), 8.32 - 8.21 (m, 2H), 8.19 - 8.12 (m, 2H), 7.25 (d, J = 8.9 Hz, 2H), 6.82 (br d, J = 11.9 Hz, 1H), 4.43 (br t, J = 4.9 Hz, 2H), 4.38 - 3.98 (m, 7H), Attorney Docket No.: 185992002240 3.67 - 3.61 (m, 2H), 3.40 - 3.32 (m, 2H), 3.26 - 3.09 (m, 2H), 2.80 (d, J = 4.5 Hz, 3H), 2.63 (t, J = 5.4 Hz, 3H), 2.36 - 1.96 (m, 4H). MS m/z (ESI) [M+H]+= 465.2. Example 247: 2-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-6- methyl-2,6-diazaspiro[3.5]nonan-5-one
Figure imgf000434_0001
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of tert-butyl N-[2-[4- [6-fluoro-7-methoxy-4-(6-methyl-5-oxo-2,6-diazaspiro[3.5]nonan-2-yl)-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate (300 mg, 518.43 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 25.97 eq). The resulting mixture was stirred at 25°C for 2 hours, filtered and evaporated under reduced pressure and the crude product was purified by prep-HPLC 11 (gradient:5%-35% over 2 min) basified by SCX cation exchange resin to give Example 247 (98.77 mg, 206.39 μmol, 39.81% yield, 100% purity) as a white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 7.89 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 12.7 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.50 (s, 1H), 4.60 (d, J = 7.6 Hz, 2H), 4.20 - 4.10 (m, 4H), 3.98 (s, 3H), 3.38 (t, J = 6.0 Hz, 2H), 3.03 (br t, J = 4.8 Hz, 2H), 2.96 (s, 3H), 2.50 (s, 3H), 2.25 (td, J = 2.8, 5.8 Hz, 2H), 1.95 - 1.84 (m, 2H). MS m/z (ESI) [M+H]+= 472.2. Example 253: 2-[4-[4-[3-[(dimethylamino) methyl]pyrrolidin-1-yl]-6-fluoro-7-methoxy-2- quinolyl]phenoxy]-N-methyl-ethanamine
Figure imgf000434_0002
According to Scheme 3 Step 3: Conditions 1 HCl: A solution of tert-butyl N-[2-[4-[4- [3-[(dimethylamino) methyl]pyrrolidin-1-yl]-6-fluoro-7-methoxy-2-quinolyl]phenoxy]ethyl]- N-methyl-carbamate (160 mg, 289.50 μmol, 1 eq) in HCl/dioxane (5 mL) was stirred at 25°C for 1 hour, concentrated and the crude material was purified by Prep-HPLC 1 (gradient:0%- 26% over 10 min) to give Example 253 (128 mg, 227.78 μmol, 78.68% yield, 100% purity, Attorney Docket No.: 185992002240 3HCl) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.86 (s, 1H), 11.06 (br s, 1H), 9.32 (br d, J = 2.8 Hz, 2H), 8.33 (br d, J = 13.3 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 8.17 (d, J = 8.9 Hz, 2H), 7.25 (d, J = 8.9 Hz, 2H), 6.85 (s, 1H), 4.43 (br t, J = 4.9 Hz, 2H), 4.32 (br dd, J = 6.2, 8.7 Hz, 1H), 4.10 - 3.95 (m, 6H), 3.40 - 3.32 (m, 2H), 3.28 (br t, J = 6.2 Hz, 2H), 2.91 - 2.83 (m, 1H), 2.80 (d, J = 4.8 Hz, 6H), 2.63 (t, J = 5.4 Hz, 3H), 2.36 - 2.25 (m, 1H), 1.95 - 1.82 (m, 1H). MS m/z (ESI) [M+H]+= 453.3. Example 254: (cis)-2-[2-[4-(azetidin-3-ylmethoxy)phenyl]-6-fluoro-7-methoxy-4-quinolyl]- 5-methyl-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one
Figure imgf000435_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of cis-tert-butyl 3- ((4-(6-fluoro-7-methoxy-4-(5-methyl-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)quinolin-2-yl)phenoxy)methyl)azetidine-1-carboxylate (140 mg, 237.01 μmol, 1 eq) in DCM (2 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 28.40 eq). The reaction solution was stirred at 25 °C for 1 hour, concentrated and the residue was purified by prep-HPLC 4 (gradient:1%-30% over 10 min) basified by SCX cation exchange resin to give Example 254 (70 mg, 138.27 μmol, 58.34% yield, 96.9% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15 (br d, J = 8.6 Hz, 2H), 7.95 (br d, J = 14.1 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.04 (br d, J = 8.6 Hz, 2H), 6.95 (s, 1H), 4.18 (br d, J = 6.7 Hz, 2H), 3.99 - 3.78 (m, 7H), 3.66 - 3.49 (m, 6H), 3.08 - 3.00 (m, 2H), 2.87 (s, 3H), 2.79 - 2.74 (m, 1H), 1.95 (br dd, J = 4.2, 13.1 Hz, 1H), 1.87 - 1.73 (m, 1H). MS m/z (ESI) [M+H]+= 491.2. Example 263: (3S) -1-[7-methoxy-2-[4-[2-(methylamino) ethoxy]phenyl]-4-quinolyl]-N- methyl-pyrrolidine-3-carboxamide
Figure imgf000435_0002
According to Scheme 3 Step 3: Conditions 1 HCl: A solution of tert-butyl N-[2-[4-[7- methoxy-4-[(3S) -3-(methylcarbamoyl) pyrrolidin-1-yl]-2-quinolyl]phenoxy]ethyl]-N- Attorney Docket No.: 185992002240 methyl-carbamate (120 mg, 224.45 μmol, 1 eq) in HCl/dioxane (4 mL) was stirred at 25°C for 1 hour, concentrated and the residue was purified by Prep-HPLC 1 (gradient:3%-33% over 20 min) to give Example 263 (110 mg, 216.77 μmol, 96.58% yield, 100% purity, 2HCl) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.47 (s, 1H), 9.26 (s, 2H), 8.43 (d, J = 9.6 Hz, 1H), 8.23 (br d, J = 4.8 Hz, 1H), 8.11 (d, J = 8.9 Hz, 2H), 7.81 (d, J = 2.3 Hz, 1H), 7.31 - 7.15 (m, 3H), 6.81 (s, 1H), 4.41 (t, J = 5.0 Hz, 2H), 4.22 - 3.99 (m, 4H), 3.94 (s, 3H), 3.41 - 3.33 (m, 2H), 3.18 (quin, J = 7.3 Hz, 1H), 2.66 - 2.60 (m, 6H), 2.35 - 2.23 (m, 1H), 2.22 - 2.10 (m, 1H). MS m/z (ESI) [M+H]+= 435.4. Example 267: 2-[4-[4- dimethyl-2,2-dioxo-2thia-3,7-diazaspiro[4.4]nonan-7-yl)-7-
Figure imgf000436_0001
methoxy-2-quinolyl]phenoxy]-N-methyl-ethanamine
Figure imgf000436_0002
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl N-[2-[4- [4-(1, 3-dimethyl-2, 2-dioxo-2thia-3, 7-diazaspiro[4.4]nonan-7-yl) -7-methoxy-2- quinolyl]phenoxy]ethyl]-N-methyl-carbamate & tert-butyl N-[2-[4-[7-methoxy-4-(3-methyl- 2, 2-dioxo-2thia-3, 7-diazaspiro[4.4]nonan-7-yl) -2-quinolyl]phenoxy]ethyl]-N-methyl- carbamate (150.00 mg, 124.22 μmol, 1 eq) in EtOAc (0.50 mL) was added HCl/EtOAc (2 M, 3.00 mL, 48.30 eq) at 20°C. The reaction mixture was stirred at 20°C for 1 hour, concentrated under reduced and the residue was purified by prep-HPLC 1 (gradient: 2-10 min 0-30%; flow 25 mL/min) basified by SCX cation exchange resin to give Example 267 (23.11 mg, 45.26 μmol, 36.43% yield, 100% purity) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.19 - 8.08 (m, 3H), 7.27 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.99 (br dd, J = 2.9, 9.3 Hz, 1H), 6.95 - 6.89 (m, 1H), 4.09 (t, J = 5.6 Hz, 2H), 3.96 - 3.82 (m, 5H), 3.72 (s, 1H), 3.53 - 3.49 (m, 1H), 3.21 (br s, 3H), 2.86 (t, J = 5.4 Hz, 2H), 2.62 - 2.57 (m, 3H), 2.36 (s, 3H), 2.20 - 1.90 (m, 2H), 1.38 - 1.26 (m, 3H) MS m/z (ESI) [M+H]+= 511.3. Example 272: 2-[6-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-2,7- diazaspiro[4.4]nonan-8-one Attorney Docket No.: 185992002240
Figure imgf000437_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl N-[2-[4- [6-fluoro-7-methoxy-4-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)-2-quinolyl]phenoxy]ethyl]-N- methyl-carbamate (100 mg, 177.10 μmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (4 M, 666.67 μL, 15.06 eq). The resulting mixture was stirred at 25°C for 1 hour, filtered and evaporated under reduced pressure and the crude product was purified by prep-HPLC 10 (gradient:2%-32% over 10 min) basified by SCX cation exchange resin to give Example 272 (41.19 mg, 88.40 μmol, 49.92% yield, 99.7% purity) as a white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 7.95 - 7.90 (m, 3H), 7.43 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.80 (s, 1H), 4.20 (t, J = 5.2 Hz, 2H), 4.00 (s, 3H), 3.90 - 3.84 (m, 2H), 3.76 (s, 2H), 3.45 (d, J = 3.3 Hz, 2H), 3.08 (t, J = 5.1 Hz, 2H), 2.54 (s, 3H), 2.51 - 2.44 (m, 2H), 2.14 (dt, J = 2.3, 6.7 Hz, 2H). MS m/z (ESI) [M+H]+= 465.3. Example 278: cis-2-(7-(methoxy-d3)-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4- yl)octahydro-4H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000437_0002
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of cis-tert-butyl (2- (4-(7-(methoxy-d3) -4-(4-oxooctahydro-2H-pyrrolo[3, 4-c]pyridin-2-yl) quinolin-2-yl) phenoxy) ethyl) (methyl) carbamate (210 mg, 382.04 μmol, 1 eq) in DCM (3 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 17.62 eq), the reaction mixture was stirred at 25°C for 1 hour. The resulting mixture was stirred at 25°C for 2 hours, filtered and evaporated under reduced pressure and the crude product was purified by prep-HPLC 8 (gradient:2%-32% over 20 min) basified by SCX cation exchange resin to give Example 278 (42.28 mg, 90.57 μmol, 23.71% yield, 96.3% purity) as a white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.19 - 8.12 (m, 3H), 7.74 (br s, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.05 (d, J = 8.9 Hz, 2H), 6.98 (dd, J = 2.8, 9.3 Hz, 1H), 6.92 (s, 1H), 4.14 (t, J = 5.4 Hz, 2H), 3.99 - 3.92 (m, 1H), 3.91 - Attorney Docket No.: 185992002240 3.83 (m, 2H), 3.55 (br d, J = 5.1 Hz, 1H), 3.24 (br dd, J = 4.4, 8.4 Hz, 2H), 3.03 - 2.98 (m, 3H), 2.77 (br dd, J = 2.1, 5.2 Hz, 1H), 2.44 (s, 3H), 1.95 - 1.87 (m, 1H), 1.74 - 1.63 (m, 1H). MS m/z (ESI) [M+H]+= 450.2. Example 284: (cis)-2-[7-ethoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000438_0001
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of cis-tert-butyl (2- (4-(7-ethoxy-4-(4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate (100 mg, 178.35 μmol, 1 eq) in DCM (1 mL) was added TFA (460.50 mg, 4.04 mmol, 0.3 mL, 22.64 eq). The reaction mixture was stirred at 25 °C for 1 hour, concentrated and the residue was purified by prep-HPLC 3 (gradient:0%-28% B over 10 min) basified by SCX cation exchange resin to give Example 284 (50.15 mg, 108.89 μmol, 61.05% yield, 100% purity) was obtained as a white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.22 (d, J = 9.4 Hz, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 2.7 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.06 (dd, J = 2.5, 9.5 Hz, 1H), 6.82 (s, 1H), 4.25 (t, J = 5.1 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 4.13 - 4.00 (m, 3H), 3.68 (dd, J = 3.8, 10.3 Hz, 1H), 3.46 - 3.39 (m, 2H), 3.22 - 3.14 (m, 3H), 2.92 - 2.82 (m, 1H), 2.59 (s, 3H), 2.00 (qd, J = 4.5, 13.7 Hz, 1H), 1.90 - 1.75 (m, 1H), 1.48 (t, J = 7.0 Hz, 3H). MS m/z (ESI) [M+H]+= 461.3. Example 292: cis-5-(7-methoxy-2-(4-(2-(methylamino)ethoxy)phenyl)quinolin-4- yl)hexahydropyrrolo[3,4-b]pyrrol-2(1H)-one
Figure imgf000438_0002
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of cis-tert-butyl(2-(4- (7-methoxy-4-(2-oxohexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl) quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate (120 mg, 0.153 mmol, 68% purity, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2.00 M, 3.00 mL) at 25°C. The mixture was stirred at Attorney Docket No.: 185992002240 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC 8 (gradient:5%-35% B over 20 min). The salt was basified by Strong Cation Exchange Resin. 1) Wash resin with deionized water 20 mL; 2) Wash resin with the salt in methanol (target was adsorbed to the resin); 3) Wash resin with deionized water until the pH of the solution is neutral; 4) Wash resin with ammonium hydroxide/methanol, target was cleaved from the resin; 5) concentration and lyophilization give Example 292 (35.0 mg, 0.0794 mmol, 51.8% yield, 98.1% purity) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.18 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 9.4 Hz, 1H), 7.89 (s, 1H), 7.30 (d, J = 2.6 Hz, 1H), 7.12 - 7.02 (m, 4H), 4.29 - 4.22 (m, 1H), 4.14 (t, J = 5.4 Hz, 2H), 3.91 (s, 3H), 3.65 ( d, J = 10.9 Hz, 1H), 3.57 - 3.52 (m, 2H), 3.47 - 3.44 (m, 1H), 3.15 - 3.05 (m, 1H), 2.98 (t, J = 5.4 Hz, 2H), 2.59 ( dd, J = 9.1, 17.1 Hz, 1H), 2.43 (s, 3H), 2.22 (dd, J = 2.4, 17.1 Hz, 1H). MS m/z (ESI) [M+H]+= 433.2. Example 299: 2-[4-[7-methoxy-4-[3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]-2- quinolyl]phenoxy]-N-methyl-ethanamine
Figure imgf000439_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl N-[2-[4- [7-methoxy-4-[3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]-2-quinolyl]phenoxy]ethyl]-N- methyl-carbamate (150 mg, 267.51 μmol, 1 eq) in dioxane (2 mL) was added HCl/dioxane (4 M, 0.5 mL, 7.48 eq). The resulting mixture was stirred at 25°C for 1 hours, concentrated and the crude product was purified by prep-HPLC 10 (gradient:1%-25% over 10.0 min ) basified by SCX cation exchange resin to give Example 299 (44.43 mg, 95.98 μmol, 35.88% yield, 99.5% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.58 (br s, 1H), 11.28 (br s, 1H), 9.33 (br s, 2H), 8.55 (br d, J = 9.5 Hz, 1H), 8.15 (d, J = 8.6 Hz, 2H), 7.90 (s, 1H), 7.25 (d, J = 8.9 Hz, 2H), 7.18 (d, J = 2.4, 9.5 Hz, 1H), 6.82 (s, 1H), 4.43 (br t, J = 4.8 Hz, 2H), 4.35 (br d, J = 1.6 Hz, 1H), 4.17 - 3.86 (m, 7H), 3.39 - 3.32 (m, 4H), 3.04 (br s, 2H), 2.84 (br s, 1H), 2.64 (t, J = 5.4 Hz, 3H), 2.32 (d, J = 3.3, 6.8 Hz, 1H), 2.10 - 1.82 (m, 6H). MS m/z (ESI)461.3[M+H]+. [M+H]+= 461.3. Attorney Docket No.: 185992002240 Example 302: (cis)-2-[8-fluoro-7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4- quinolyl]-3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000440_0001
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of cis-tert-butyl (2- (4-(8-fluoro-7-methoxy-4-(4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate (80 mg, 141.68 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 95.02 eq). The resulting mixture was stirred at 25°C for 12 hours, filtered and concentrated and the crude product was purified by prep-HPLC 10 (gradient:0%-30% over 10.0 min) basified by SCX cation exchange resin to give Example 302 (35.67 mg, 76.79 μmol, 54.20% yield, 100% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.19 (d, J = 9.0 Hz, 2H), 8.06 (br d, J = 10.0 Hz, 1H), 7.74 (br s, 1H), 7.30 (t, J = 8.9 Hz, 1H), 7.06 (br d, J = 8.8 Hz, 2H), 6.95 (s, 1H), 4.14 (br t, J = 5.4 Hz, 2H), 4.03 - 3.94 (m, 5H), 3.91 (br d, J = 8.1 Hz, 2H), 3.61 - 3.56 (m, 1H), 3.26 - 3.22 (m, 1H), 3.05 - 2.96 (m, 3H), 2.78 (br s, 1H), 2.43 (s, 3H), 1.94 - 1.87 (m, 1H), 1.69 (br s, 1H). MS m/z (ESI) [M+H]+= 465.4. Example 304: 7-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-3-methyl- 1,7-diazaspiro[4.4]nonan-2-one
Figure imgf000440_0002
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of tert-butyl N-[2-[4- [7-methoxy-4-(3-methyl-2-oxo-1,7-diazaspiro[4.4]nonan-7-yl)-2-quinolyl]phenoxy]ethyl]-N- methyl-carbamate (80 mg, 142.68 μmol, 1 eq) in DCM (1 mL) was added TFA (307.00 mg, 2.69 mmol, 0.2 mL, 18.87 eq) at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM : MeOH : NH3.H2O = 10:1:0.1) to give Example 304 (30.8 mg, 66.87 μmol, 46.87% yield, 100% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ Attorney Docket No.: 185992002240 (ppm): 8.21 (d, J = 16.4 Hz, 1H), 8.17 - 8.09 (m, 3H), 7.25 (d, J = 2.5 Hz, 1H), 7.04 ( d, J = 8.2 Hz, 2H), 6.98 (d, J = 9.4 Hz, 1H), 6.87 (d, J = 4.2 Hz, 1H), 4.09 (t, J = 5.6 Hz, 2H), 3.89 (s, 4H), 3.83 - 3.74 (m, 2H), 3.64 ( dd, J = 9.8, 14.4 Hz, 1H), 2.91 - 2.84 (m, 2H), 2.44 - 2.30 (m, 4H), 2.15 - 2.00 (m, 2H), 1.81 - 1.65 (m, 1H), 1.08 (t, J = 6.4 Hz, 3H). MS m/z (ESI) [M+H]+= 461.4. Example 309: 7-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]-3-methyl- 1,7-diazaspiro[4.4]nonan-2-one
Figure imgf000441_0001
According to Scheme 3 Step 3: Conditions 2 TFA: To a solution of give tert-butyl (2- (4-(7-methoxy-4-(4-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate (150 mg, 281.62 μmol, 1 eq) in DCM (2 mL) was added TFA (32.11 mg, 281.62 μmol, 20.92 μL, 1 eq). The resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by prep-HPLC (Waters Xbridge BEH C18 100*25mm*5um;mobile phase: [H2O(0.05%HCl)-ACN];gradient:1%-29% B over 10.0 min) to give the Example 309 (17.96 mg, 40.65 μmol, 14.44% yield, 97.9% purity) as a yellow gum. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.30 - 8.14 (m, 3H), 8.10 - 8.03 (m, 1H), 8.06 (d, J = 9.4 Hz, 1H), 7.85 - 7.81 (m, 1H), 7.82 (s, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.09 - 7.02 (m, 4H), 4.16 (br t, J = 5.3 Hz, 2H), 3.90 (s, 3H), 3.85 (br d, J = 10.0 Hz, 1H), 3.69 (br d, J = 8.3 Hz, 2H), 3.65 - 3.62 (m, 2H), 3.56 (br d, J = 2.3 Hz, 3H), 3.05 - 3.01 (m, 2H), 2.45 (s, 3H). MS m/z (ESI) [M+H]+= 433.3. Example 315: (cis)-6-fluoro-7-methoxy-4-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)quinoline
Figure imgf000441_0002
Attorney Docket No.: 185992002240 According to Scheme 1 Step 5: Conditions 4 Buchwald: To a screw-cap vial equipped with a magnetic stir bar was added 4-chloro-6-fluoro-7-methoxy-2-(6-pyrrolidin-1-yl-3- pyridyl) quinoline (200 mg, 558 μmol, 1 eq) and dioxane (4 mL) and cis-5-methyloctahydro- 1H-pyrrolo[3,4-c]pyridine (140 mg, 998 μmol, 1.8 eq) and Cs2CO3 (550 mg, 1.69 mmol, 3 eq) and SPhos Pd G3 (50 mg, 64.0 μmol, 0.1 eq) sequentially. After work-up the reaction mixture was diluted with DCM/MeOH (10 mL, 10/1) and purified by silica gel chromatography (100-200 mesh silica gel, DCM/MeOH =10/1) to give crude product. The crude product was purified by prep-HPLC 2 (gradient:2%-26% over 10 min) basified by SCX cation exchange resin to give Example 315 (68 mg, 147 μmol, 64.8% yield, 99.9% purity) as yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.65 (d, J = 2.2 Hz, 1H), 8.13 (dd, J = 2.4, 9.0 Hz, 1H), 8.00 (d, J = 13.8 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 6.75 (s, 1H), 6.62 (d, J = 8.8 Hz, 1H), 4.01 (s, 3H), 3.95 - 3.76 (m, 3H), 3.75 - 3.67 (m, 1H), 3.53 (br t, J = 6.5 Hz, 4H), 2.69 - 2.49 (m, 4H), 2.49 - 2.41 (m, 1H), 2.41 - 2.34 (m, 1H), 2.32 (s, 3H), 2.08 (br t, J = 6.7 Hz, 4H), 1.88 (tt, J = 4.3, 8.1 Hz, 1H), 1.80 - 1.68 (m, 1H). MS m/z (ESI) [M+H]+= 462.2. Example 331: (3aS,6aS)-5-(6-fluoro-7-methoxy-2-(4-(2- (methylamino)ethoxy)phenyl)quinolin-4-yl)hexahydropyrrolo[3,4-b]pyrrol-2(1H)-one
Figure imgf000442_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl (2-(4-(6- fluoro-7-methoxy-4-((3aS,6aS)-2-oxohexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate (60.0 mg, 97.0% purity, 105 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 6.00 mL, 115 eq) at 25°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduce presser to give a residue, The residue was purified by prep-HPLC 8 (gradient:1%-27% B over 20 min). The salt was basified by Strong Cation Exchange Resin. 1) Wash resin with deionized water 20 mL; 2) Wash resin with the salt in methanol (target was adsorbed to the resin); 3) Wash resin with deionized water until the pH of the solution is neutral; 4) Wash resin with ammonium hydroxide/methanol, target was cleaved from the resin; 5) concentration and lyophilization give Example 311 (16.0 mg, 35.5 μmol, 33.9% yield, 100% purity) as a yellow solid. 1H Attorney Docket No.: 185992002240 NMR (400 MHz, methanol-d4) δ (ppm): 8.16 (d, J = 8.80 Hz, 2H), 7.91 (s, 1H), 7.79 (d, J = 13.2 Hz, 1H), 7.49 (d, J = 8.80 Hz, 1H), 7.16 (s, 1H), 7.06 (d, J = 8.80 Hz, 2H), 4.29 - 4.21 (m, 1H), 4.10 (t, J = 5.60 Hz, 2H), 4.00 (s, 3H), 3.64 ( d, J = 10.8 Hz, 1H), 3.58 - 3.48 (m, 2H), 3.41 (dd, J = 4.92, 10.8 Hz, 1H), 3.13 - 3.06 (m, 1H), 2.88 (t, J = 5.52 Hz, 2H), 2.59 ( dd, J = 9.32, 17.2 Hz, 1H), 2.37 (s, 3H), 2.21 (dd, J = 2.40, 17.2 Hz, 1H). MS m/z (ESI) [M+H]+= 451.2. Example 332: (3aR,7aS)-2-[7-methoxy-2-[4-[2-(methylamino)ethoxy]phenyl]-4-quinolyl]- 3,3a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one
Figure imgf000443_0001
According to Scheme 3 Step 3: Conditions 1 HCl: To a solution of tert-butyl (2-(4-(7- methoxy-4-((3aR,7aS)-4-oxooctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)quinolin-2- yl)phenoxy)ethyl)(methyl)carbamate (150 mg, 274.40 μmol, 1 eq) in MeOH (2 mL) was added HCl/dioxane (2 M, 2 mL, 14.58 eq). The reaction solution was stirred at 25°C for 1 hour, concentrated under vacuum nand the crude product was purified by prep-HPLC 10 (gradient:1%-25% over 10.0 min ) basified by SCX cation exchange resin to give Example 332 (95 mg, 208.92 μmol, 76.14% yield, 98.2% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.42 (s, 1H), 9.31 - 9.07 (m, 2H), 8.48 (d, J = 9.5 Hz, 1H), 8.12 (d, J = 8.8 Hz, 2H), 7.83 (br s, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.28 - 7.19 (m, 3H), 6.85 (s, 1H), 4.41 (t, J = 5.0 Hz, 2H), 4.34 - 4.14 (m, 3H), 3.99 - 3.87 (m, 4H), 3.39 - 3.23 (m, 4H), 3.11 (q, J = 6.8 Hz, 1H), 2.95 - 2.78 (m, 1H), 2.67 - 2.62 (m, 3H), 2.00 - 1.87 (m, 1H), 1.79 - 1.65 (m, 1H). MS m/z (ESI) [M+H]+= 447.3. The compounds in Table 3 were synthesized using methods similar to those disclosed elsewhere herein. Attorney Docket No.: 185992002240 Table 3.
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Biological Examples Exemplary assays for evaluating the biological activity of compounds described herein are described below. Example B-1 - Induced Pluripotent Stem Cells (iPSCs) Culture and Differentiation iPSCs were maintained in mTesR Plus (Stem Cell Technologies) on Geltrex-coated cell culture plates. Cells were passaged as colonies using PBS + 0.5 mM EDTA. For differentiation to spinal motor neurons, a previously described protocol was adapted (Baxi, et al. Nature Neuroscience 2022, hereby incorporated by reference in its entirety). iPSCs were dissociated to single cells using Accutase (Stem Cell Technologies) and plated at 50,000 cells/cm2 in mTesR Plus with 10 uM Y-27632 (Stem Cell Technologies). The following day, cells were transitioned a basal media of 1:1 IMDM/F12 containing 1% non-essential amino acids, 1% B27, 1% N2, Anti/Anti (ThermoFisher) and the following small molecules: 0.2 µM LDN-193189, 3 µM CHIR-99021, and 10 µM SB-431542 (Cayman Chemical; Stage 1 media). After 6 days, cells were dissociated and split 1:4 in basal medium containing 0.2 µM LDN-193189, 3 µM CHIR99021, 10 µM SB-431542, 0.1 µM all-trans retinoic acid, 1 µM SAG, and 10 µM Y-27632 (Cayman Chemical; Stage 2 media). On day 12 of culture, cells were dissociated using Accutase and cryopreserved. To mature motor neuron progenitors, cells were thawed on plates sequentially coated with PEI followed by 1% Geltrex in basal media containing 0.5 µM all-trans retinoic acid, Attorney Docket No.: 185992002240 0.1 µM SAG, 0.1 µM Compound E, 2.5 µM DAPT, 20 ng/mL L-ascorbic acid, 0.1 µM dibutyryl cyclic-AMP, 10 ng/mL of BDNF and GDNF, and 10 µM Y-27632 (Stage 3 media). From day 14 post-thaw onwards, neurons were maintained in basal medium containing 10 ng/mL BDNF and GDNF (Stage 4 media). All treatments were performed on day 16 post- thaw. Example B-2 - iPSC-derived Motor Neuron Condensate Assay C-mods demonstrate dose-dependent modulation of TDP-43 cytoplasmic condensates in iPSC-derived motor neurons. Neurons (3000/well in PhenoPlate 384 well plates) were cultured in Stage 4 media (described above) for 48 h prior to stress and compound treatment. On day 16 post-thaw from the motor neuron progenitor stage, media was aspirated and replaced with 30 µL/well of Stage 4 media containing 10 µg/mL puromycin. Cells were immediately treated with compounds (2-fold dilutions beginning at 15 uM) using an Echo 650 acoustic dispenser with a consistent 0.16% DMSO across conditions. 30 µM digitonin was added to 6 wells evenly distributed across the plate to establish a 100% cytotoxicity control for normalization of a multiplexed lactate dehydrogenase (LDH) assay. Neurons were fixed by adding 30 µL of 8% PFA in PBS exactly 24 h post-treatment. Cells were subsequently washed in PBS, permeabilized for 15 min at RT with PBS + 0.1% Triton X-100 + 1% BSA, and primary antibodies (table below) were incubated overnight in permeabilization buffer. The following day, plates were washed twice in PBS + 0.05% Tween-20 and incubated with secondary antibodies (table below) for 1 h at RT. Plates were washed twice with PBS + 0.05% Tween-20, followed by once with PBS, sealed and stored at 4 °C until imaging. All images were acquired using an Opera Phenix High-Content Screening System (Perkin Elmer) with the confocal setting and 2-3 planes per field-of-view. Table B-1. Primary Antibodies
Figure imgf000490_0001
Table B-2. Secondary Antibodies
Figure imgf000490_0002
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Figure imgf000491_0001
Example B-3 - Quantitative PCR (qPCR) Diverse cellular stressors trigger TDP-43 to exit the nucleus and phase separate into cytoplasmic heterogeneous biomolecular condensates. A consequence of this subcellular translocation is that TDP-43-dependent functions such as pre-mRNA splicing of STMN2 and POLDIP3 are negatively impacted. C-mods demonstrate dose-dependent restoration of STMN2 and POLDIP3 splicing in iPSC-derived motor neurons. Stress and compound treatment in iPSC-MNs were administered as described above in “iPSC-derived motor neuron condensate assay ”. Following 24 h of stress and compound, media was aspirated and cells were lysed using the Cells-to-CT Lysis buffer (ThermoFisher Scientific, cat# 4391851C) using half the manufacturer’s recommended volume. cDNA was generated using the Cells-to-CT Advanced RT Reagents (ThermoFisher Scientific, cat# A39110) using a quarter of the manufacturer’s recommended volume. cDNA was stored at - 20 °C until use. Multiplex qPCR was performed in a 10 µL 384 well format using TaqMan Fast Advanced Master Mix (ThermoFisher Scientific, cat# 4444558) according to manufacturer’s protocol. Primers were ordered from Integrated DNA Technologies (IDT) and the sequences are described below. GAPDH_CY5 Forward: GAAGATGGTGATGGGATTTC Reverse: GAAGGTGAAGGTCGGAGTC Probe: CAAGCTTCCCGTTCTCAGCC (/5Cy5/CAAGCTTCC/TAO/CGTTCTCAGCC/3IAbRQSp/) STMN2_HEX For detection of full length STMN2 mRNA. Amplicon spans exon 2-3 junction. Forward: AGCTGTCCATGCTGTCACTG Reverse: GGTGGCTTCAAGATCAGCTC Probe: ATTTGCTTCACTTCCATATCATCGTAAGTATAGATG (/5HEX/ATTTGCTTC/ZEN/ACTTCCATATCATCGTAAGTATAGATG/3IABkFQ/ ) Attorney Docket No.: 185992002240 POLDIP3-EX3exclusion-FAM For detection of isoform of POLDIP3 exon3 exclusion mRNA. Amplicon spans exon 2-4 junction. Forward: ACTGCTTAGCCCAGCCATGT Reverse: GCTCACCAAAACCATCCAGAA Probe: ATGGTATAGCTTCCGTTCCTACTAAAC (/56-FAM/ATGGTATAG/ZEN/CTTCCGTTCCTACTAAAC/31ABkFQ/) The above procedure was performed for the compounds in Table B-3, for which the results are provided. The symbol “****” indicates a EC50 or IC50 less than or equal to 0.10 μM. The symbol “***” indicates an EC50 or IC50 greater than 0.10 μM and less than or equal to 0.50 μM. The symbol “**” indicates an EC50 or IC50 greater than 0.50 μM and less than or equal to 1.0 μM. The symbol “*” indicates a EC50 or IC50 greater than 1.0 μM and less than or equal to 5.0 μM. The symbol “NA” indicates no activity. The symbol
Figure imgf000492_0001
indicates no data is available. Table B-3.
Figure imgf000492_0002
Attorney Docket No.: 185992002240
Figure imgf000493_0001
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Figure imgf000494_0001
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Figure imgf000495_0001
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Figure imgf000496_0001
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Figure imgf000497_0001
Attorney Docket No.: 185992002240
Figure imgf000498_0001
Attorney Docket No.: 185992002240
Figure imgf000499_0001
Attorney Docket No.: 185992002240
Figure imgf000500_0001
Example B-4 – Traumatic brain injury model All animal experiments were performed according to the National Institutes of Health (Bethesda, MD, USA) guidelines for the care and use of laboratory animals. Animals were weighed upon arrival to facility, acclimated for 2 weeks, tested for portosystemic shunts, and weighed everyday throughout the in-life portion of the study. Test articles were delivered to wild-type C57Bl/6J mice (8-12 weeks of age) by oral (p.o.) or subcutaneous (s.c.) administration 3-4h prior to surgery. Mice were anesthetized in an induction chamber at 5% isoflurane and maintained at 1.5-2.5% isoflurane via face mask throughout the surgery. Eyes were protected with Viscotears, body temperature was monitored, and animals were hydrated s.c. with warm Ringer’s lactate solution. Anesthetized mice were positioned in a stereotaxic frame where a unilateral craniotomy of 3 mm diameter was performed at bregma -2.0 mm and lateral + 2.0 mm from the midline. A single controlled cortical impact (CCI; PintPoint Precision Cortical Impactor, Hatteras Instruments, Inc.) was delivered using a 2.5 mm diameter tip traveling at 3.0 m/s to a depth of 1.0 mm, with a dwell time of 50 ms. After impact, the bone flap was replaced using dental cement, and the wound was sutured. Control sham animals underwent surgery and craniotomy, but no cortical impact. Buprenorphine (0.05 mg/kg, s.c.) was administered 30 Attorney Docket No.: 185992002240 min before surgery and for 2 days following surgery (every 8 hours). General animal welfare, body weight and wound recovery was evaluated daily. Mice were terminally anesthetized with pentobarbital (180 mg/kg intraperitoneal) 7 days following TBI. Terminal body weights, plasma, and cerebrospinal fluid (CSF) were collected. Animals were then transcardially perfused with ice-cold heparinized saline. Brains were processed for immunohistochemistry. NfL was measured from CSF using Quanterix Simoa NF-Light 2 Advantage assay kit (#104073) according to the manufacturer’s protocol. Plasma proteomics analysis was performed by SomaLogic for 1500 target SomaScan. The above procedure was performed for exemplary compounds of formula (II-D-2), as defined herein, for which the results are provided in Table B-4. * indicates P<0.05 relative to TBI alone (Row 2). ** indicates P<0.01 relative to TBI alone (Row 2). *** indicates P<0.001 relative to TBI alone (Row 2). **** indicates P<0.0001 relative to TBI alone (Row 2). No stars indicate no statistically significant changes. “a.u.” represents arbitrary units. Table B-4.
Figure imgf000501_0001
All publication, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entireties, to the same extent as if each were incorporated by reference individually. It is to be understood that, while the disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

Attorney Docket No.: 185992002240 CLAIMS What is claimed is: 1. A compound of formula (I)
Figure imgf000502_0001
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1 and R2 are taken together with the N to which they are attached to form a saturated 4- to 5- membered monocyclic heterocyclyl, saturated 7- to 10-membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl, wherein the saturated 4- to 5-membered monocyclic heterocyclyl, saturated 7- to 9-membered fused heterocyclyl, or saturated 7- to 10-membered spirocyclic heterocyclyl is optionally substituted with one or more R3; each R3 is independently halo, C1-6alkyl, oxo, -OR12, -N(Rx)(Ry), -CN, or -C(=O)N(R13)(R14), wherein the C1-6alkyl of R3 is optionally substituted with R3a; Ring A is 4- to 8-membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 8-membered cycloalkenyl, 4- to 8-membered unsaturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4, and the 4- to 8-membered unsaturated heterocyclyl or 5- to 6-membered heteroaryl of Ring A comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R4 is independently halo, C1-6alkyl, or -OR12; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R5)(C1-6alkyl)-; R5 is H, C1-6alkyl, or C3-8cycloalkyl, wherein the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), or - OR12, and Attorney Docket No.: 185992002240 the C3-8cycloalkyl is optionally substituted with one or more R5b; R6 is -OR12, -O-(3- to 12-membered N-containing heterocyclyl), -O-(5- to 6-membered N- containing heteroaryl), -N(Rx)(Ry), -N(R13)C(=O)R14, -N(R13)C(=O)N(R13)R14, - N(R13)C(=O)OR14, -OC(=O)N(R13)R14, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R13)(R14), - N(R13)S(=O)2R14, -S(=O)N(R13)R14, -S(=O)2N(R13)(R14), -(C3-8cycloalkyl)N(Rx)(Ry), or 3- to 8-membered N-containing heterocyclyl, wherein the -O-(3- to 8-membered N-containing heterocyclyl), -O-(5- to 6-membered N- containing heteroaryl), or 3- to 8-membered N-containing heterocyclyl of R6 is optionally substituted with one or more R6b, -C(=O)R14, -C(=O)N(R13)(R14), or - C(=O)OR14, and the 3- to 8-membered N-containing heterocyclyl of R6 optionally further comprises 1 or 2 atoms selected from the group consisting of N, O, and S; R7 is H or halo; R8 and R9 are each independently H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(=O)R14, - N(R13)C(=O)OR14, -N(R13)C(=O)N(R13)R14, -OC(=O)R14, -OC(=O)OR14, - OC(=O)N(R13)R14, -C(=O)R14, -C(=O)OR14, -C(=O)N(R13)(R14), C3-8cycloalkyl, or 3- to 8- membered heterocyclyl, wherein the C1-6alkyl of R8 or R9 is optionally substituted by one or more R7a, the 3- to 8-membered heterocyclyl of R8 is optionally substituted with one or more R7b, and the 3- to 8-membered heterocyclyl of R8 comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; R10 is H; each R1a, R3a, R4a, R6a, or R7a is independently -OR12, -N(Rx)(Ry), -C(=O)N(R13)(R14), or 3- to 8-membered heterocyclyl; each R1b, R3b, R4b, R5b, R6b, or R7b is independently halo, C1-6alkyl, -OR11, or -N(Rx)(Ry), wherein the C1-6alkyl of R1b, R3b, R4b, R5b, R6b, or R7b is optionally substituted by -OR12, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R11 is independently H or C1-6alkyl; each R12 is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, or 5- to 10- membered heteroaryl, Attorney Docket No.: 185992002240 wherein the C1-6alkyl of R12 is optionally substituted with one or more halo, deuterium, -O(C1-6alkyl), or -N(Rx)(Ry); each R13 is independently H or C1-6alkyl; each R14 is independently H, C1-6alkyl, C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R14 is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -N(Rx)(Ry), C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12- membered heterocyclyl, and the C3-8cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or 3- to 12-membered heterocyclyl of R14 is optionally substituted with halo, C1-6alkyl, or -N(Rx)(Ry); each R15 is independently H or C1-6alkyl; and each Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with halo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl), wherein when Ring A is phenyl, then -L-R6 is not -NH2 or -OCH3. 2. The compound of claim 1, wherein the compound is a compound of formula (II)
Figure imgf000504_0001
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1 is N or CH, and n is 0, 1, 2, or 3. Attorney Docket No.: 185992002240 3. The compound of claim 2 wherein the compound is a compound of formula (II-A)
Figure imgf000505_0001
pharmaceutically acceptable salt of any of the foregoing. 4. The compound of claim 2, wherein the compound is a compound of formula (II-B)
Figure imgf000505_0002
pharmaceutically acceptable salt of any of the foregoing. 5. The compound of claim 2, wherein the compound is a compound of formula (II-C)
Figure imgf000505_0003
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Attorney Docket No.: 185992002240 6. The compound of claim 1, wherein the compound is a compound of formula (III)
Figure imgf000506_0001
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1 is N or CH; and n is 0, 1, 2, or 3. 7. The compound of claim 6, wherein the compound is a compound of formula (III-B)
Figure imgf000506_0002
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 8. The compound of any of claims 1-7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8 is H, halo, C1-6alkyl, -OR12, -N(Rx)(Ry), -N(R13)C(O)R14, -N(R13)C(O)OR14, - N(R13)C(O)N(R13)R14, -C(O)N(R13)(R14), or C3-6cycloalkyl, wherein the C1-6alkyl of R8 is optionally substituted by one or more R7a; and R9 is H, halo, C1-6alkyl, -OR12, -CN, or C3-6cycloalkyl, wherein the C1-6alkyl of R9 is optionally substituted by one or more R7a. Attorney Docket No.: 185992002240 9. The compound of claim 1, wherein the compound is a compound of formula (IV):
Figure imgf000507_0001
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X2, X4 and X5 are each independently C, N, O or S; X3 and X6 are each independently C or N; and n is 0, 1, 2, or 3. 10. The compound of claim 9, wherein the compound is a compound of formula (IV-A):
Figure imgf000507_0002
stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 11. The compound of claim 1, wherein Ring A is phenyl or 5- to 6-membered heteroaryl, wherein phenyl or 5- to 6-membered heteroaryl of Ring A is optionally substituted by one or more R4. 12. The compound of claim 11, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is selected from the group consisting of phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furan, thiophene, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, and triazinyl. 13. The compound of claim 12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is phenyl, thiazolyl, or pyridinyl. Attorney Docket No.: 185992002240 14. The compound of any of claims 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1 and R2 are taken together with the N to which they are attached to form a saturated 4- to 5-membered monocyclic heterocyclyl optionally substituted with one or more R3. 15. The compound of any of claims 1-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the R1 and R2 are taken together with the N to which they are attached to form an azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl of R1 and R2 is optionally substituted with one or more R3. 16. The compound of claim 14 or 15, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R3 is independently - OH, C1-6alkyl, C1-6alkoxy, or -N(Rx)(Ry) wherein the C1-6alkyl of the R3 is optionally substituted with R3a. 17. The compound of claim 16, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R3 is independently - OH, C1-4alkyl, C1-4alkoxy, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -NH(C3- 6cycloalkyl), or -N(C1-4alkyl)(C3-6cycloalkyl), wherein the C1-4alkyl of the R3 is optionally substituted with R3a. 18. The compound of claim 17, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R3 is independently - OH, -CH3, -CH2OH, -OCH3, or -NH2. 19. The compound of claim 14 or 15, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group consisting
Figure imgf000508_0001
Attorney Docket No.: 185992002240
Figure imgf000509_0001
20. The compound of any of claims 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the R1 and R2 are taken together with the N to which they are attached to form a saturated 7- to 10-membered fused heterocyclyl optionally substituted with one or more R3. 21. The compound of claim 20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R3 is independently C1-6alkyl or oxo. 22. The compound of claim 21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R3 is independently - CH3 or oxo. 23. The compound of claim 20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group
Figure imgf000509_0002
Attorney Docket No.: 185992002240 24. The compound of any of claims 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the R1 and R2 are taken together with the N to which they are attached to form a saturated 7- to 10-membered spirocyclic heterocyclyl optionally substituted with one or more R3. 25. The compound of claim 24, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R3 is halo. 26. The compound of claim 25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R3 is F. 27. The compound of claim 24, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the R1 and R2 are taken together with the N to which they are attached to form a heterocyclyl selected from the group
Figure imgf000510_0001
28. The compound of any of claims 1, 2, 6, 9, or 11, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R4 is independently halo or -O-(C1-6alkyl). 29. The compound of claim 28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R4 is independently halo or -OCH3. 30. The compound of any of claims 1-29, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5 is H, C1-6alkyl, or C3- 8cycloalkyl, wherein Attorney Docket No.: 185992002240 the C1-6alkyl of R5 is optionally substituted with one or more halo, -N(Rx)(Ry), -OR12, and the C3-8cycloalkyl of R5 is optionally substituted with one or more R5b. 31. The compound of any of claims 1-30, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5 is H, C1-6alkyl, or C3- 8cycloalkyl. 32. The compound of any of claims 1-31, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5 is H or C1-6alkyl. 33. The compound of any of claims 1-32, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5 is H. 34. The compound of any of claims 1-29, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is a bond or -O-(C1- 6alkyl)-. 35. The compound of any of claims 1-29, or 34, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is a bond or -O- (CH2CH2)-. 36. The compound of any of claims 1-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6 is -N(Rx)(Ry). 37. The compound of claim 1-36, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6 is selected from the group consisting
Figure imgf000511_0001
38. The compound of any of claims 1-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6 is -N(R13)C(O)R14, - N(R13)C(O)OR14, -N(R13)C(O)N(R13)R14, -C(O)N(R13)(R14), or -C(O)(C1-6alkyl)N(R13)(R14). 39. The compound of any of claims 1-35 or 38, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6 is -N(R13)C(O)R14 or - C(O)(C1-6alkyl)N(R13)(R14). Attorney Docket No.: 185992002240 40. The compound of any of claims 1-35 or 39, or a stereoisomer or tautomer thereof, or a 6
Figure imgf000512_0001
pharmaceutically acceptable salt of any of the foregoing, wherein R is or
Figure imgf000512_0002
. 41. The compound of any of claims 1-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6 is 3- to 12-membered N- containing heterocyclyl optionally substituted with one or more R6b. 42. The compound of any of claims 1-35 or 41, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is a bond and R6 is 3- to 12-membered N-containing heterocyclyl optionally substituted with one or more R6b. 43. The compound of any of claims 1-35, 41, or 42, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6 is azetidinyl, pyrrolidinyl, or piperazinyl, wherein the azetidinyl, pyrrolidinyl, or piperazinyl is optionally substituted with one or more R6b. 44. The compound of any of claims 1-35 or 41-43, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6 is selected from the
Figure imgf000512_0003
45. The compound of any of claims 1-44, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8 and R9 are each independently H, halo, -N(Rx)(Ry), -OR11, -N(R13)C(O)R14, or -N(R13)C(O)OR14. Attorney Docket No.: 185992002240 46. The compound of claim 45, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8 and R9 are each independently H, halo, -NH2, -N(C1-6alkyl)(C1-6alkyl), -O(C1-6alkyl), -NHC(O)(5- to 6- membered aryl), or -NHC(O)O(C1-6alkyl), wherein the 5- to 6-membered aryl of -NHC(O)(5- to 6-membered aryl) is optionally substituted with -N(C1-6alkyl)(C1-6alkyl). 47. The compound of claim 46, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8 and R9 are each independently H, F, Cl, -NH2, -N(CH3)(CH3), -OCH3, -NHC(O)(phenyl), or - NHC(O)O(CH2CH3), wherein the phenyl of -NHC(O)(phenyl) is substituted with -N(CH3)(CH3). 48. The compound of any of claims 1-47, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8 and R9 are each H. 49. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from Table 1. 50. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from compounds 1 to 68 of Table 1. 51. A pharmaceutical composition comprising a compound of any of claims 1-50, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients or carriers. 52. A method for treating a disease or condition mediated by TDP-43, comprising administering to an individual in need thereof a compound of any of claims 1-50, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 51. 53. The method of claim 52, wherein said disease or condition mediated by TDP-43 is a neurological disease or condition. 54. The method of claim 53, wherein the neurological disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), Attorney Docket No.: 185992002240 inclusion body myositis, Perry syndrome, corticobasal degeneration, spinocerebellar ataxia type 3, and amyotrophic lateral sclerosis (ALS). 55. The method of claim 53 or 54, wherein the neurological disease or condition is traumatic brain injury (TBI). 56. The method of claim 53 or 54, wherein the neurological disease or condition is frontotemporal dementia (FTD). 57. The method of claim 53 or 54, wherein the neurological disease or condition is amyotrophic lateral sclerosis (ALS). 58. The method of any of claims 53, 54, or 57, wherein the neurological disease or condition is sporadic amyotrophic lateral sclerosis or C9ORF72 amyotrophic lateral sclerosis. 59. The method of any of claims 52-58, wherein neurodegeneration is reduced. 60. A method of modulating TDP-43, comprising contacting a cell with an effective amount of a compound of any of claims 1-50, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 51, wherein modulating TDP-43 comprises modulating TDP-43 incorporation into condensates, modulating TDP-43 binding to RNA in condensates, modulating TDP-43 aggregation, or modulating TDP43 protein-protein interactions. 61. A method of modulating TDP-43 driven gene expression levels, comprising contacting a cell with an effective amount of a compound of any of claims 1-50, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 51. 62. The method of claim 61, wherein the gene expression levels are for STMN2. 63. The method of claim 61, wherein the gene expression levels are for POLDIP3. 64. The compound of any of claims 1-50, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 51 for use in the treatment of a disease or condition mediated by TDP-43. Attorney Docket No.: 185992002240 65. Use of a compound of any of claims 1-50, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition mediated by TDP-43. 66. A kit, comprising (i) a compound of any one of claims 1-50, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 51 and (ii) instructions for use in treating a TDP-43 mediated disease or condition in an individual in need thereof.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4402961A (en) * 1980-06-20 1983-09-06 Pharmindustrie Derivatives of 1-(2-,3- or 4-quinolyl)-2- or -3-(2- or 3-piperidyl or -pyrrolidinyl) ethanone or propanone, and their utilization as antiarrhythmics, anticonvulsivants and for the treatment of anxiety
WO2012016082A1 (en) * 2010-07-30 2012-02-02 Oncotherapy Science, Inc. Quinoline derivatives and melk inhibitors containing the same
US9718803B2 (en) * 2010-05-13 2017-08-01 Amgen Inc. Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
WO2021035101A1 (en) * 2019-08-22 2021-02-25 Biohaven Therapeutics Ltd. Molecules that bind to tdp-43 for the treatment of amyotrophic lateral sclerosis and related disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4402961A (en) * 1980-06-20 1983-09-06 Pharmindustrie Derivatives of 1-(2-,3- or 4-quinolyl)-2- or -3-(2- or 3-piperidyl or -pyrrolidinyl) ethanone or propanone, and their utilization as antiarrhythmics, anticonvulsivants and for the treatment of anxiety
US9718803B2 (en) * 2010-05-13 2017-08-01 Amgen Inc. Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
WO2012016082A1 (en) * 2010-07-30 2012-02-02 Oncotherapy Science, Inc. Quinoline derivatives and melk inhibitors containing the same
WO2021035101A1 (en) * 2019-08-22 2021-02-25 Biohaven Therapeutics Ltd. Molecules that bind to tdp-43 for the treatment of amyotrophic lateral sclerosis and related disorders

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem 19 August 2012 (2012-08-19), ANONYMOUS: "4-(Azetidin-1-yl)quinoline | C12H12N2 ", XP093336377, Database accession no. CID 58864151 *
DATABASE PubChem 29 March 2010 (2010-03-29), ANONYMOUS: "2-(4-Methoxyphenyl)-4-(1-pyrrolidinyl)quinoline | C20H20N2O", XP093336379, Database accession no. CID 45051409 *

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